Light-activated conjugated polymer nanoparticles to defeat pathogens associated with bovine mastitis.

Bovine mastitis (BM) represents a significant challenge in the dairy industry. Limitations of conventional treatments have prompted the exploration of alternative approaches, such as photodynamic inactivation (PDI). In this study, we developed a PDI protocol to eliminate BM-associated pathogens using porphyrin-doped conjugated polymer nanoparticles (CPN). The PDI-CPN protocol was evaluated in four mastitis isolates of Staphylococcus and in a hyper-biofilm-forming reference strain. The results in planktonic cultures demonstrated that PDI-CPN exhibited a bactericidal profile upon relatively low light doses (∼9.6 J/cm2). Furthermore, following a seven-hour incubation period, no evidence of cellular reactivation was observed, indicating a highly efficient post-photodynamic inactivation effect. The successful elimination of bacterial suspensions encouraged us to test the PDI-CPN protocol on mature biofilms. Treatment using moderate light dose (∼64.8 J/cm2) reduced biofilm biomass and metabolic activity by up to 74% and 88%, respectively. The impact of PDI-CPN therapy on biofilms was investigated using scanning electron microscopy (SEM), which revealed nearly complete removal of the extracellular matrix and cocci. Moreover, ex vivo studies conducted on bovine udder skin demonstrated the efficacy of the therapy in eliminating bacteria from these scaffolds and its potential as a prophylactic method. Notably, the histological analysis of skin revealed no signs of cellular degeneration, suggesting that the protocol is safe and effective for BM treatment. Overall, this study demonstrates the potential of PDI-CPN in treating and preventing BM pathogens. It also provides insights into the effects of PDI-CPN on bacterial growth, metabolism, and survival over extended periods, aiding the development of effective control strategies and the optimization of future treatments.

Comparison Between Corticocancellous Allograft and Bovine Xenograft for Sinus Augmentation: A Radiographic, Histologic, and Histomorphometric Clinical Study.

Sinus floor augmentation is one of the most common approaches to obtain sufficient bone availability for placing implants in cases with severe bone atrophy in the posterior maxilla. Several bone substitutes are indicated for sinus augmentation, but they may achieve different clinical outcomes. This study aims to compare bovine bone mineral (BBM) with freeze-dried bone allograft (FDBA) in a two-stage lateral window sinus grafting approach. Twenty patients received a lateral window sinus elevation with either FDBA or BBM. Postoperative graft height was measured with CBCT. Implants were placed 6 months later, at which time biopsy samples were taken for histologic analysis and new CBCT scans were performed to measure graft height. The mean height reduction at 6 months was 20.27% ± 4.94% for FDBA samples and 5.36% ± 2.41% for BBM samples. The histologic analysis revealed a mean ratio of newly formed bone of 43.70% ± 5.29% for the FDBA group and 38.11% ± 4.03% for the BBM group. The FDBA group also showed a higher amount of residual biomaterial (17.25% ± 10.10%) and connective tissue (14.63% ± 4.38%) compared to the BBM group (15.53% ± 5.42% and 13.11% ± 4.42%, respectively). The differences between groups were statistically significant for the height reduction and newly formed bone (P ≤ .05) but not for the amounts of residual biomaterial and nonmineralized connective tissue (P ≥ .05). Six months after performing a lateral window sinus elevation, the percentage of newly formed bone was significantly higher when using FDBA than when using BBM, although the graft height reduction was also significantly higher for the FDBA group.

Comparision between cortico-cancellous allograft and bovine xenograft for sinus augmentation: a radiographic, histologic and histomorphometric clinical study.

Sinus floor augmentation is one of the most used approaches to obtain sufficient bone availability to place dental implants in cases with severe bone atrophy in the posterior maxilla. Several bone substitutes are indicated for sinus augmentation but they may obtain different clinical outcomes. This study aims to compare bovine bone mineral (BBM) with freeze dried bone allograft (FDBA) in two- stage lateral window sinus grafting approach. 20 patients received a lateral window sinus lift with either FDBA or BBM. Post-operative graft height was measured with a cone-beam computerized tomography (CBCT). 6 months later implants were placed. Biopsies were taken for histological analysis and new CBCts were performed to measure graft height at this point. 6 months after procedure, there was a height reduction of 20,27 ± 4,94 % for the FDBA sample and 5,36 ± 2,41% for the BBM group. The histological analysis revealed a ratio of newly formed bone of 43,70 ± 5,29% for the FDBA and 38,11 ± 4,03% for the BBM group. The FDBA also showed a higher amount of residual biomaterial 17,25 ± 10,10% and connective tissue 14,63 ± 4,38% compared to the BBM 15,53 ± 5,42% and 13,11 ± 4,42%. The differences between groups were statistically significant for the height reduction and for the newly formed bone (p ≤ 0.05) but not for the residual biomaterial amount and the non-mineralized connective tissue (p ≥ 0.05). It could be concluded that the percentage of newly formed bone 6 months after performing a lateral window sinus lift using FDBA was significantly higher than when using BBM, although the graft height reduction was also significantly higher for the FDBA group.

Características y factores asociados a la mortalidad en pacientes con COVID-19 traqueostomizados: estudio de cohorte retrospectivo en un hospital de Tacna, Perú / Characteristics and factors associated with mortality in tracheostomized patients with COVID-19: a retrospective cohort study in a hospital in Tacna, Peru

RESUMEN Objetivo. Describir las principales características demográficas, clínicas, laboratoriales y terapéuticas e identificar si están asociados con la mortalidad en pacientes traqueostomizados. Material y métodos. Estudio de cohorte retrospectiva en pacientes adultos con diagnóstico de COVID-19, ingresados a UCI (Unidad de Cuidados Intensivos) y que requirieron traqueostomía. Se extrajeron datos demográficos, clínicos, laboratoriales y de tratamiento de las historias clínicas de pacientes que ingresaron al Hospital III Daniel Alcides Carrión de Tacna. Para el análisis de supervivencia se empleó el modelo de riesgos proporcionales de Cox y se calcularon los cocientes de riesgo instantáneos (HR) con sus intervalos de confianza al 95% (IC95%). Resultados. Se evaluaron 73 pacientes, el 72,6% eran hombres, las comorbilidades más comunes fueron obesidad (68,5%), diabetes mellitus tipo 2 (35,6%) e hipertensión arterial (34,2%). El 37% de los participantes fallecieron durante la estancia en UCI. La mediana de tiempo desde la intubación hasta la traqueostomía y la duración de esta fue 17 (RIC: 15−21) y 21 (RIC: 3−39) días, respectivamente. El análisis multivariado mostró que los factores asociados a mortalidad, fueron presentar un valor de procalcitonina > 0,50 ng/dL en el momento de la traqueostomía (HRa: 2,40 IC95%: 1,03−5,59) y el nivel de PaO2/FiO2 menor o igual a 150 mmHg, (HRa: 4,44 IC95%: 1,56−12,60). Conclusiones. Los factores asociados a mortalidad al momento de realizar la traqueostomía fueron presentar un valor de procalcitonina > 0,50 ng/dL y un cociente PaO2/FiO2 menor o igual a 150 mmHg.

ABSTRACT Objective: We aimed to describe the main demographic, clinical, laboratory and therapeutic characteristics and to identify whether they are associated with mortality in tracheostomized patients. Material and methods. Retrospective cohort study in adult patients diagnosed with COVID-19, admitted to ICU (Intensive Care Unit) and requiring tracheostomy. Demographic, clinical, laboratory and treatment data were obtained from the medical records of patients admitted to Hospital III Daniel Alcides Carrión in Tacna. The Cox proportional hazards model was used for survival analysis and hazard ratios (HR) with their 95% confidence intervals (95%CI) were calculated. Results. We evaluated 73 patients, 72.6% were men, the most common comorbidities were obesity (68.5%), type 2 diabetes mellitus (35.6%), and arterial hypertension (34.2%). Thirty-seven percent of the participants died during their stay at the ICU. The median time from intubation to tracheostomy and the duration of tracheostomy was 17 (RIC: 15-21) and 21 (RIC: 3-39) days, respectively. Multivariate analysis showed that the factors associated with mortality were procalcitonin > 0.50 ng/dL at the time of tracheostomy (HRa: 2.40 95%CI: 1.03-5.59) and a PaO2/FiO2 ratio less than or equal to 150 mmHg (HRa: 4.44 95%CI: 1.56-12.60). Conclusions. The factors associated with mortality at the time of tracheostomy were procalcitonin > 0.50 ng/dL and a PaO2/FiO2 ratio less than or equal to 150 mmHg.

Dynamic Regulatory Assessment: Unpacking the Process Reveals Readiness to Pilot for Europe-An EFPIA View.

The medicines regulatory network of the European Economic Area comprises 30 countries, their National Competent Authorities (NCA), and the European Medicines Agency (EMA). The NCAs and EMA are involved at different stages of the medicine life cycle; not all are engaged in a particular medicine's development discussions. As a result, knowledge management (ie, acquisition and transfer between medicine developer and the NCAs) is fragmented and inefficient. Dynamic regulatory assessment (DRA), a regulatory science concept developed by the European Federation of Pharmaceutical Industries and Associations (EFPIA), could drive increased connectedness supporting more continuous knowledge building. DRA works via iterative release and assessment of discrete data packets (DDPs) at mutually agreed milestones during development, culminating in more efficient development and faster authorization. This commentary seeks to build on an earlier article by unpacking the DRA concept, with a particular focus on DDPs. Its aim is to show how DDPs can support efficient and predictable release of data to encourage development and assessment of promising medicines, and it makes the case for piloting the DRA concept with European regulators now.

Metronomic Photodynamic Therapy with Conjugated Polymer Nanoparticles in Glioblastoma Tumor Microenvironment.

Alternative therapies such as photodynamic therapy (PDT) that combine light, oxygen and photosensitizers (PSs) have been proposed for glioblastoma (GBM) management to overcome conventional treatment issues. An important disadvantage of PDT using a high light irradiance (fluence rate) (cPDT) is the abrupt oxygen consumption that leads to resistance to the treatment. PDT metronomic regimens (mPDT) involving administering light at a low irradiation intensity over a relatively long period of time could be an alternative to circumvent the limitations of conventional PDT protocols. The main objective of the present work was to compare the effectiveness of PDT with an advanced PS based on conjugated polymer nanoparticles (CPN) developed by our group in two irradiation modalities: cPDT and mPDT. The in vitro evaluation was carried out based on cell viability, the impact on the macrophage population of the tumor microenvironment in co-culture conditions and the modulation of HIF-1α as an indirect indicator of oxygen consumption. mPDT regimens with CPNs resulted in more effective cell death, a lower activation of molecular pathways of therapeutic resistance and macrophage polarization towards an antitumoral phenotype. Additionally, mPDT was tested in a GBM heterotopic mouse model, confirming its good performance with promising tumor growth inhibition and apoptotic cell death induction.

Reusable antimicrobial antibiotic-free dressings obtained by photopolymerization.

In recent years significant efforts have been made to develop new materials for wound dressing with improved healing properties. However, the synthesis methods usually employed to this end are often complex or require several steps. We describe here the synthesis and characterization of antimicrobial reusable dermatological wound dressings based on N-isopropylacrylamide co-polymerized with [2-(Methacryloyloxy) ethyl] trimethylammonium chloride hydrogels (NIPAM-co-METAC). The dressings were obtained with a very efficient single-step synthesis procedure based on visible light (455 nm) by photopolymerization. To this end, F8BT nanoparticles of the conjugated polymer (poly(9,9-dioctylfluorene-alt-benzothiadiazole) - F8BT) were used as macro-photoinitiators, and a modified silsesquioxane was employed as crosslinker. Dressings obtained by this simple and gentle method show antimicrobial and wound healing properties, without the incorporation of antibiotics or any other additives. The physical and mechanical properties of these hydrogel-based dressings were evaluated, as well as their microbiological properties, through in vitro experiments. Results show that dressings with a molar ratio of METAC of 0.5 or higher exhibit high swelling capacity, appropriate water vapor transmission rate values, stability and thermal response, high ductility and adhesiveness. In addition, biological tests showed that the dressings have significant antimicrobial capacity. The best inactivation performance was found for hydrogels synthesized with the highest METAC content. The dressings were tested several times with fresh bacterial cultures, showing a bacterial kill efficiency of 99.99 % even after three repetitions in a row, employing the same dressing, demonstrating the intrinsic bactericidal property of the materials and their reusability. In addition, the gels show low hemolytic effect, high dermal biocompatibility and noticeable wound healing effects. Overall results demonstrate that some specific hydrogel formulations have potential application as dermatological dressings for wound healing and disinfection.

Characteristics and factors associated with mortality in tracheostomized patients with COVID-19: a retrospective cohort study in a hospital in Tacna, Peru. / Características y factores asociados a la mortalidad en pacientes con COVID-19 traqueostomizados: estudio de cohorte retrospectivo en un hospital de Tacna, Perú.

OBJECTIVE: We aimed to describe the main demographic, clinical, laboratory and therapeutic characteristics and to identify whether they are associated with mortality in tracheostomized patients. MATERIAL AND METHODS.: Retrospective cohort study in adult patients diagnosed with COVID-19, admitted to ICU (Intensive Care Unit) and requiring tracheostomy. Demographic, clinical, laboratory and treatment data were obtained from the medical records of patients admitted to Hospital III Daniel Alcides Carrión in Tacna. The Cox proportional hazards model was used for survival analysis and hazard ratios (HR) with their 95% confidence intervals (95%CI) were calculated. RESULTS.: We evaluated 73 patients, 72.6% were men, the most common comorbidities were obesity (68.5%), type 2 diabetes mellitus (35.6%), and arterial hypertension (34.2%). Thirty-seven percent of the participants died during their stay at the ICU. The median time from intubation to tracheostomy and the duration of tracheostomy was 17 (RIC: 15-21) and 21 (RIC: 3-39) days, respectively. Multivariate analysis showed that the factors associated with mortality were procalcitonin > 0.50 ng/dL at the time of tracheostomy (HRa: 2.40 95%CI: 1.03-5.59) and a PaO2/FiO2 ratio less than or equal to 150 mmHg (HRa: 4.44 95%CI: 1.56-12.60). CONCLUSIONS.: The factors associated with mortality at the time of tracheostomy were procalcitonin > 0.50 ng/dL and a PaO2/FiO2 ratio less than or equal to 150 mmHg.

OBJETIVO.: Describir las principales características demográficas, clínicas, laboratoriales y terapéuticas e identificar si están asociados con la mortalidad en pacientes traqueostomizados. MATERIAL Y MÉTODOS.: Estudio de cohorte retrospectiva en pacientes adultos con diagnóstico de COVID-19, ingresados a UCI (Unidad de Cuidados Intensivos) y que requirieron traqueostomía. Se extrajeron datos demográficos, clínicos, laboratoriales y de tratamiento de las historias clínicas de pacientes que ingresaron al Hospital III Daniel Alcides Carrión de Tacna. Para el análisis de supervivencia se empleó el modelo de riesgos proporcionales de Cox y se calcularon los cocientes de riesgo instantáneos (HR) con sus intervalos de confianza al 95% (IC95%). RESULTADOS.: Se evaluaron 73 pacientes, el 72,6% eran hombres, las comorbilidades más comunes fueron obesidad (68,5%), diabetes mellitus tipo 2 (35,6%) e hipertensión arterial (34,2%). El 37% de los participantes fallecieron durante la estancia en UCI. La mediana de tiempo desde la intubación hasta la traqueostomía y la duración de esta fue 17 (RIC: 15−21) y 21 (RIC: 3−39) días, respectivamente. El análisis multivariado mostró que los factores asociados a mortalidad, fueron presentar un valor de procalcitonina > 0,50 ng/dL en el momento de la traqueostomía (HRa: 2,40 IC95%: 1,03−5,59) y el nivel de PaO2/FiO2 menor o igual a 150 mmHg, (HRa: 4,44 IC95%: 1,56−12,60). CONCLUSIONES.: Los factores asociados a mortalidad al momento de realizar la traqueostomía fueron presentar un valor de procalcitonina > 0,50 ng/dL y un cociente PaO2/FiO2 menor o igual a 150 mmHg.

Determination of PaO2/FiO2 after 24 h of invasive mechanical ventilation and ΔPaO2/FiO2 at 24 h as predictors of survival in patients diagnosed with ARDS due to COVID-19.

Introduction: Acute respiratory distress syndrome (ARDS) due to Coronavirus Disease 2019 (COVID-19) causes high mortality. The objective of this study is to determine whether the arterial pressure of oxygen/inspiratory fraction of oxygen (PaO2/FiO2) 24 h after invasive mechanical ventilation (IMV) and the difference between PaO2/FiO2 at 24 h after IMV and PaO2/FiO2 before admission to IMV (ΔPaO2/FiO2 24 h) are predictors of survival in patients with ARDS due to COVID-19. Methods: A retrospective cohort study was conducted that included patients with ARDS due to COVID-19 in IMV admitted to the intensive care unit (ICU) of a hospital in southern Peru from April 2020 to April 2021. The ROC curves and the Youden index were used to establish the cut-off point for PaO2/FiO2 at 24 h of IMV and ΔPaO2/FiO2 at 24 h associated with mortality. The association with mortality was determined by Cox regression, calculating the crude (cHR) and adjusted (aHR) risk ratios, with their respective 95% confidence intervals (95% CI). Results: Two hundred patients were analyzed. The average age was 54.29 years, 79% were men, and 25.5% (n = 51) died. The cut-off point calculated for PaO2/FiO2 24 h after IMV and ΔPaO2/FiO2 24 h was 222.5 and 109.5, respectively. Those participants with a value below the cut-off point of ΔPaO2/FiO2 24 h and PaO2/FiO2 24 h after IMV had higher mortality, aHR = 3.32 (CI 95% [1.82-6.07]) and aHR = 2.87 (CI 95% [1.48-5.57]) respectively. Conclusion: PaO2/FiO2 24 h after IMV and ΔPaO2/FiO2 24 h in patients diagnosed with ARDS due to COVID-19 on IMV were associated with higher hospital mortality. These findings are helpful to identify those patients with a higher risk of dying on admission to the ICU.

Sweet light o' mine: Photothermal and photodynamic inactivation of tenacious pathogens using conjugated polymers.

Each year a rising number of infections can not be successfully treated owing to the increasing pandemic of antibiotic resistant pathogens. The global shortage of innovative antibiotics fuels the emergence and spread of drug resistant microbes. Basic research, development, and applications of alternative therapies are urgently needed. Since the 90´s, light-mediated therapies have promised to be the next frontier combating multidrug-resistance microbes. These platforms have demonstrated to be a reliable, rapid, and efficient alternative to eliminate tenacious pathogens while avoiding the emergence of resistance mechanisms. Among the materials showing antimicrobial activity triggered by light, conjugated polymers (CPs) have risen as the most promising option to tackle this complex situation. These materials present outstanding characteristics such as high absorption coefficients, great photostability, easy processability, low cytotoxicity, among others, turning them into a powerful class of photosensitizer (PS)/photothermal agent (PTA) materials. Herein, we summarize and discuss the advances in the field of CPs with applications in photodynamic inactivation and photothermal therapy towards bacteria elimination. Additionally, a section of current challenges and needs in terms of well-defined benchmark experiments and conditions to evaluate the efficiency of phototherapies is presented.

Selective Photo-Assisted Eradication of Triple-Negative Breast Cancer Cells through Aptamer Decoration of Doped Conjugated Polymer Nanoparticles.

Photodynamic therapy (PDT) may be an excellent alternative in the treatment of breast cancer, mainly for the most aggressive type with limited targeted therapies such as triple-negative breast cancer (TNBC). We recently generated conjugated polymer nanoparticles (CPNs) as efficient photosensitizers for the photo-eradication of different cancer cells. With the aim of improving the selectivity of PDT with CPNs, the nanoparticle surface conjugation with unique 2'-Fluoropyrimidines-RNA-aptamers that act as effective recognition elements for functional surface signatures of TNBC cells was proposed and designed. A coupling reaction with carbodiimide was used to covalently bind NH2-modified aptamers with CPNs synthetized with two polystyrene-based polymer donors of COOH groups for the amide reaction. The selectivity of recognition for TNBC membrane receptors and PDT efficacy were assayed in TNBC cells and compared with non-TNBC cells by flow cytometry and cell viability assays. Furthermore, in vitro PDT efficacy was assayed in different TNBC cells with significant improvement results using CL4, sTN29 and sTN58 aptamers compared to unconjugated CPNs and SCR non-specific aptamer. In a chemoresistance TNBC cell model, sTN58 was the candidate for improving labelling and PDT efficacy with CPNs. We proposed sTN58, sTN29 and CL4 aptamers as valuable tools for selective TNBC targeting, cell internalization and therapeutic improvements for CPNs in PDT protocols.

Dynamic Regulatory Assessment: evolving the European Regulatory Framework for the Benefit of Patients and Public Health-an EFPIA View.

The European Union regulatory framework supports development, review, authorization, and maintenance of medicines to benefit public health; however, many elements are 2 decades old and undergoing review. Scrutiny was triggered by the coronavirus disease 2019 pandemic, the need to support future innovative medicines, the digital transformation of data exchange, and the need to address efficiency and capacity limitations. There are also ongoing evolutions in regulatory science for medicines (eg, cell and gene therapies), medical device combinations, and software, as well as the need to fully leverage contemporary information technology (IT). Important initiatives to address these challenges include the European Medicines Agency (EMA) Regulatory Science Strategy,1 the EU Regulatory Network Strategy,2 and the Big Data Steering Group,3 alongside European Commission-led initiatives such as the Pharmaceutical Strategy.4 Dynamic regulatory assessment (DRA) is a concept that seeks to integrate these various elements to re-imagine regulatory review interactions across the product life cycle. DRA calls for iterative regulatory dialogue, data submission, and evidence assessment, enabled by contemporary IT. DRA will facilitate iterative interaction and data assessment as it accumulates over a product's life cycle, bringing significant efficiencies for all product types. The DRA concept primarily evolved through dialogue within working groups of the European Federation of Pharmaceutical Industries and Associations. This article describes the long-term vision of the European Federation of Pharmaceutical Industries and Associations and outlines important strategic elements of progress, including: aligning on a multi-stakeholder vision for DRA in the European Union and across regions; leveraging learnings from ongoing initiatives; and advancing IT, governance, and standards considerations. Ultimately, DRA should consider outcomes that deliver optimal benefits for patients in the European Union and worldwide.

Factors associated with mortality due to COVID-19 in patients from a public hospital in Tacna, Peru. / Factores asociados a la muerte por COVID-19 en pacientes admitidos en un hospital público en Tacna, Perú.

OBJECTIVE: To describe the clinical, laboratory and treatment characteristics of COVID-19 patients and to determine the factors associated with mortality during hospital stay. Materials and Methods: Retrospective cohort study of adult COVID-19 inpatients. The clinical, laboratory and treatment data were obtained from the medical records of patients from the Hospital Nivel III Daniel Alcides Carrión in Tacna. For the survival analysis we used the Cox proportional hazards model, and we calculated crude and adjusted hazard ratios (HR) with 95% confidence intervals (95% CI). RESULTS: We evaluated 351 patients; 74.1% of them were men. The most common comorbidities were obesity (31.6%), hypertension (27.1%) and diabetes mellitus (24.5%). The median time of hospitalization was 8 days (IQR: 4-15). From the total of patients, 32.9% died during follow-up. The multivariate analysis showed an increased risk of dying associated with the following: age ≥65 years, HR = 3.55 (95% CI: 1.70-7.40); increase in lactate dehydrogenase >720 U/L, HR = 2.08 (95% CI: 1.34-3.22); and oxygen saturation less than 90%, mainly when it was less than 80%, HR = 4.07 (95% CI: 2.10-7.88). In addition, the use of colchicine during treatment showed a protective effect, HR = 0.46 (95% CI: 0.23-0.91). CONCLUSIONS: Risk factors for mortality due to COVID-19 included being older than 65 years, having oxygen saturation less than 90%, and elevated lactate dehydrogenase >720 U/L; colchicine treatment could improve the prognosis of patients.

OBJETIVO: Describir las características demográficas, clínicas, laboratoriales y de tratamiento de pacientes hospitalizados por la COVID-19 y determinar los factores asociados a la mortalidad hospitalaria. MATERIALES Y MÉTODOS: Estudio de cohorte retrospectivo de pacientes adultos hospitalizados por la COVID-19. Se extrajeron datos demográficos, clínicos, laboratoriales y de tratamiento de las historias clínicas de pacientes que ingresaron al Hospital III Daniel Alcides Carrión de Tacna. Para el análisis de supervivencia se empleó el modelo de riesgos proporcionales de Cox y se calcularon los cocientes de riesgo instantáneos (HR) crudos y ajustados con sus respectivos intervalos de confianza al 95% (IC 95%). RESULTADOS: Se evaluó a 351 pacientes, el 74,1% eran hombres; las comorbilidades más comunes fueron obesidad (31,6%), hipertensión (27,1%) y diabetes mellitus (24,5%). La mediana de tiempo de hospitalización fue 8 días (RIC: 4-15). El 32,9% falleció durante el seguimiento. El análisis multivariado mostró un aumento del riesgo de morir asociado a la edad ≥65 años, HR = 3,55 (IC 95%: 1,70-7,40); al incremento de lactato deshidrogenasa >720 U/L, HR = 2,08 (IC 95%: 1,34-3,22); y a la saturación de oxígeno por debajo del 90%, principalmente cuando fue menor al 80%, HR = 4,07 (IC 95%: 2,10-7,88). Además, el uso de colchicina en el tratamiento tuvo un efecto protector, HR = 0,46 (IC 95%: 0,23-0,91). CONCLUSIONES: Los factores asociados a muerte por la COVID-19 incluyeron ser mayor de 65 años, tener saturación de oxígeno menor de 90% y elevación del lactato deshidrogenasa >720 U/L; el tratamiento con colchicina podría mejorar el pronóstico de los pacientes.

Iron Oxide Incorporated Conjugated Polymer Nanoparticles for Simultaneous Use in Magnetic Resonance and Fluorescent Imaging of Brain Tumors.

Conjugated polymer nanoparticles (CPNs) have emerged as advanced polymeric nanoplatforms in biomedical applications by virtue of extraordinary properties including high fluorescence brightness, large absorption coefficients of one and two-photons, and excellent photostability and colloidal stability in water and physiological medium. In addition, low cytotoxicity, easy functionalization, and the ability to modify CPN photochemical properties by the incorporation of dopants, convert them into excellent theranostic agents with multifunctionality for imaging and treatment. In this work, CPNs were designed and synthesized by incorporating a metal oxide magnetic core (Fe3O4 and NiFe2O4 nanoparticles, 5 nm) into their matrix during the nanoprecipitation method. This modification allowed the in vivo monitoring of nanoparticles in animal models using magnetic resonance imaging (MRI) and intravital fluorescence, techniques widely used for intracranial tumors evaluation. The modified CPNs were assessed in vivo in glioblastoma (GBM) bearing mice, both heterotopic and orthotopic developed models. Biodistribution studies were performed with MRI acquisitions and fluorescence images up to 24 h after the i.v. nanoparticles administration. The resulting IONP-doped CPNs were biocompatible in GBM tumor cells in vitro with an excellent cell incorporation depending on nanoparticle concentration exposure. IONP-doped CPNs were detected in tumor and excretory organs of the heterotopic GBM model after i.v. and i.t. injection. However, in the orthotopic GBM model, the size of the nanoparticles is probably hindering a higher effect on intratumorally T2-weighted images (T2WI) signals and T2 values. The photodynamic therapy (PDT)-cytotoxicity of CPNs was not either affected by the IONPs incorporation into the nanoparticles.

Tratamiento con Tocilizumab en COVID-19 crítico: Reporte de un centro hospitalario / Tocilizumab treatment in critical COVID-19: Report from a hospital center

RESUMEN Se realizó un estudio descriptivo en el que se evaluaron las características clínicas y laboratoriales en la evolución de pacientes con diagnóstico de síndrome de distrés respiratorio agudo (SDRA) secundario a infección por SARS-CoV-2 y que recibieron Tocilizumab. Veinticuatro pacientes recibieron Tocilizumab, la mayoría eran varones (95,8 %), la comorbilidad más frecuente fue obesidad (33,3 %), al momento de recibir Tocilizumab la mediana de PaO2/FiO2 fue 159,5 (RIC 114,5-255,3). Veintiún (87,5 %) pacientes presentaron mejoría clínica y 3 (12,5 %) fallecieron. Quince pacientes (62,5 %) desarrollaron hepatotoxicidad, la mayoría de grado 3 (33,3 %) y tres (12,5 %) pacientes presentaron injuria hepática grado 4. Once pacientes (45,8 %) presentaron sobreinfección bacteriana, siendo el germen más frecuente Acinetobacter baumannii. Luego de la administración de Tocilizumab más de la mitad de los pacientes presentó una reacción adversa, a pesar de ello la mortalidad fue baja y la mayoría tuvo una mejora clínica.

ABSTRACT A descriptive study was carried out, in which clinical and laboratory characteristics were evaluated in patients with a diagnosis of acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 infection and who received Tocilizumab. Twenty- four patients received Tocilizumab, the majority were male (95.8%), the most frequent comorbidity was obesity (33.3%). At the time of receiving Tocilizumab the median PAO2 / FiO2 was 159.5 (IQR 114.5-255, 3). Twenty-one (87.5%) patients presented clinical improvement and 3 (12.5%) died. Fifteen patients (62.5%) developed hepatotoxicity, the majority grade 3 (33.3%) and three (12.5%) patients presented grade 4 liver injury. Eleven patients (45.8%) presented bacterial superinfection, the more common organism being Acinetobacter baumannii. After the administration of Tocilizumab, more than half of the patients presented an adverse reaction; despite this, mortality was low, and the majority had a clinical improvement.

Isolation and initial characterization of human glioblastoma cells resistant to photodynamic therapy.

Glioblastoma is the most severe form of brain cancer. Despite multimodal therapy combining surgery, radiotherapy and chemotherapy, prognosis of patients is dismal. It has been observed that the surgical resection guided by photosensitizer fluorescence followed by photodynamic therapy (PDT) prolongs the average survival in patients with glioblastoma. The main problem with all oncological treatments, including PDT, is the presence of resistant cells. The objective of this study was to isolate and perform an initial characterization of human glioblastoma cells resistant to PDT employing methyl-5-aminolevulinic acid. We obtained resistant cells from the T98 G cell line. Resistant populations accumulated less photosensitizer, formed spheroids of higher number of cells, had higher tumorigenic capacity, and expressed higher mRNA levels of fibroblastic growth factor receptor (FGFR), epidermal growth factor receptor (EGFR) and ß-platelet-derived growth factor receptor (ßPDGFR) than parental cells. The studies of glioblastoma resistance to PDT would help to better understand the causes of tumor recurrence after PDT and to develop new therapeutic proposals in this field of oncology.

Factores asociados a la muerte por COVID-19 en pacientes admitidos en un hospital público en Tacna, Perú

Objetivo: Describir las características demográficas, clínicas, laboratoriales y de tratamiento de pacientes hospitalizados por la COVID-19 y determinar los factores asociados a la mortalidad hospitalaria. Materiales y métodos: Estudio de cohorte retrospectivo de pacientes adultos hospitalizados por la COVID-19. Se extrajeron datos demográficos, clínicos, laboratoriales y de tratamiento de las historias clínicas de pacientes que ingresaron al Hospital III Daniel Alcides Carrión de Tacna. Para el análisis de supervivencia se empleó el modelo de riesgos proporcionales de Cox y se calcularon los cocientes de riesgo instantáneos (HR) crudos y ajustados con sus respectivos intervalos de confianza al 95% (IC 95%). Resultados: Se evaluó a 351 pacientes, el 74,1% eran hombres; las comorbilidades más comunes fueron obesidad (31,6%), hipertensión (27,1%) y diabetes mellitus (24,5%). La mediana de tiempo de hospitalización fue 8 días (RIC: 4-15). El 32,9% falleció durante el seguimiento. El análisis multivariado mostró un aumento del riesgo de morir asociado a la edad ≥65 años, HR = 3,55 (IC 95%: 1,70-7,40); al incremento de lactato deshidrogenasa >720 U/L, HR = 2,08 (IC 95%: 1,34-3,22); y a la saturación de oxígeno por debajo del 90%, principalmente cuando fue menor al 80%, HR = 4,07 (IC 95%: 2,10-7,88). Además, el uso de colchicina en el tratamiento tuvo un efecto protector, HR = 0,46 (IC 95%: 0,23-0,91). Conclusiones: Los factores asociados a muerte por la COVID-19 incluyeron ser mayor de 65 años, tener saturación de oxígeno menor de 90% y elevación del lactato deshidrogenasa >720 U/L; el tratamiento con colchicina podría mejorar el pronóstico de los pacientes.

Objective: To describe the clinical, laboratory and treatment characteristics of COVID-19 patients and to determine the factors associated with mortality during hospital stay. Materials and Methods: Retrospective cohort study of adult COVID-19 inpatients. The clinical, laboratory and treatment data were obtained from the medical records of patients from the Hospital Nivel III Daniel Alcides Carrión in Tacna. For the survival analysis we used the Cox proportional hazards model, and we calculated crude and adjusted hazard ratios (HR) with 95% confidence intervals (95% CI). Results: We evaluated 351 patients; 74.1% of them were men. The most common comorbidities were obesity (31.6%), hypertension (27.1%) and diabetes mellitus (24.5%). The median time of hospitalization was 8 days (IQR: 4-15). From the total of patients, 32.9% died during follow-up. The multivariate analysis showed an increased risk of dying associated with the following: age ≥65 years, HR = 3.55 (95% CI: 1.70-7.40); increase in lactate dehydrogenase >720 U/L, HR = 2.08 (95% CI: 1.34-3.22); and oxygen saturation less than 90%, mainly when it was less than 80%, HR = 4.07 (95% CI: 2.10-7.88). In addition, the use of colchicine during treatment showed a protective effect, HR = 0.46 (95% CI: 0.23-0.91). Conclusions: Risk factors for mortality due to COVID-19 included being older than 65 years, having oxygen saturation less than 90%, and elevated lactate dehydrogenase >720 U/L; colchicine treatment could improve the prognosis of patients.

Photodynamic therapy of Glioblastoma cells using doped conjugated polymer nanoparticles: An in vitro comparative study based on redox status.

Due to their superb light absorption and photostability conjugated polymer nanoparticles are promising photosensitizers (PS) for their use in Photodynamic therapy (PDT). Recently, we developed metallated porphyrin-doped conjugated polymer nanoparticles (CPNs) for PDT that efficiently eliminate tumor cells through reactive oxygen species (ROS) mediated photoinduced damage of apoptotic nature. These nanoaggregates act as densely packed multi-chromophoric systems having exceptional light harvesting and (intra-particle) energy transfer capabilities which lead to efficient photosensitized formation of ROS. In general, three key components; light, PS, and oxygen; are considered in the prediction of the PDT outcome. However, recent studies led to the discovery of a profound genetic heterogeneity among glioblastoma (GBM) cells which include the adaptation to ROS. Thus, tumor heterogeneity and their associated difference in sensitivity to ROS-producing therapeutic agents must be considered in the design of PDT protocols for the prediction of its outcome. In this study, anticancer activity through ROS-mediated PDT using CPNs was compared in three GBM cell lines with different initial redox status. T98G cells were the most effective incorporating nanoparticles but also were the most resistant to CPN-PDT effect. In part, this feature could be attributed to the differential basal and PDT-induced antioxidant enzyme levels found in these cells measured by gene expression analysis. Furthermore, considering that cell-specific antioxidant enzyme status is a significant feature of GBM heterogeneity, establishing its correlation with CPN-PDT outcome might be important for designing novel and improved CPN-based treatments.

Trojan horse monocyte-mediated delivery of conjugated polymer nanoparticles for improved photodynamic therapy of glioblastoma.

Aim: To assess monocyte-based delivery of conjugated polymer nanoparticles (CPNs) for improved photodynamic therapy (PDT) in glioblastoma (GBM). Materials & methods: Human monocyte cells (THP-1) and murine monocytes isolated from bone marrow (mBMDMs) were employed as stealth CPN carriers to penetrate into GBM spheroids and an orthotopic model of the tumor. The success of PDT, using this cell-mediated targeting strategy, was determined by its effect on the spheroids. Results: CPNs did not affect monocyte viability in the absence of light and did not show nonspecific release after cell loading. Activated monocytes incorporated CPNs in a higher proportion than monocytes in their naive state, without a loss of cellular functionality. In vitro PDT efficacy using cell-mediated delivery was superior to that using non vehiculized CPNs. Conclusion: CPN-loaded monocytes could efficiently deliver CPNs into GBM spheroids and the orthotopic model. Improved PDT in spheroids was confirmed using this delivery strategy.

Photodynamic Inactivation of ESKAPE Group Bacterial Pathogens in Planktonic and Biofilm Cultures Using Metallated Porphyrin-Doped Conjugated Polymer Nanoparticles.

Photodynamic inactivation (PDI) protocols using photoactive metallated porphyrin-doped conjugated polymer nanoparticles (CPNs) and blue light were developed to eliminate multidrug-resistant pathogens. CPNs-PDI protocols using varying particle concentrations and irradiation doses were tested against nine pathogenic bacterial strains including antibiotic-resistant bacteria of the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens group. The bactericidal effect was achieved in methicillin-resistant Staphylococus aureus (S. aureus) strains using low light doses (9.6-14.4 J/cm2), while Gram-negative bacteria required a higher light dose (28.8 J/cm2). The bacteria-CPN interaction was studied through flow cytometry, taking advantage of the intrinsic CPN fluorescence, demonstrating that CPNs efficiently bind to the bacterial envelope. Finally, the performance of CPNs-PDI was explored in biofilms; good antibiofilm ability and almost complete eradication were observed for S. aureus and Escherichia coli biofilms, respectively, using confocal microscopy. Overall, we demonstrated that CPNs-PDI is an efficient tool not only to kill superbugs as sessile cells but also to disrupt and eradicate biofilms of highly relevant pathogenic bacterial species.