Photoredox C(2)-Arylation of Indole- and Tryptophan-Containing Biomolecules.

We introduce a novel and straightforward methodology for photoredox arylation of an indole scaffold using aryldiazonium salts under mild and metal-free conditions. Our approach enables the regioselective and chemoselective introduction of several aryl groups to the C(2) position of indoles and tryptophan, even in competition with other amino acids. This approach extends to the late-stage functionalization of peptides and lysozyme, heralding the unprecedented arylation of tryptophan residues in wild-type proteins and offering broad utility in chemical biology.

Occurrence of musculoskeletal disorders, burnout, and psychological suffering in Brazilian nursing workers: A cross-sectional study.

Background: Musculoskeletal disorders (MSDs) pose a pervasive concern among nursing professionals due to the high physical workload. Simultaneously, the complex relationship between MSDs and mental health outcomes in this population remains an area of significant interest and importance. Objective: This study aimed to investigate the occurrence of MSDs and their relationships with burnout and psychological suffering within the nursing workforce. Methods: A cross-sectional study was conducted in 2020 involving 291 nursing professionals in Brazil. Standardized questionnaires were employed to gather information on MSDs, mental health outcomes, and pertinent work-related factors. Robust statistical analyses were conducted to ascertain the prevalence of MSDs, establish associations between MSDs and mental health outcomes, and delineate the influence of work-related factors on these associations. Statistical analysis was performed using the R software. Results: The study revealed a significant prevalence of musculoskeletal injuries (MSIs) among nursing workers, focusing on regions that include the lower back, upper back, neck, and shoulders. Individuals with MSIs in the lower back showed a marked increase in emotional exhaustion (p = 0.02), as did those with MSIs in the upper back (p <0.01) and depersonalization (p = 0.07). On the other hand, nursing professionals who reported MSIs in the neck and shoulders had considerably higher scores in emotional exhaustion (p <0.01 and p = 0.01, respectively) and depersonalization (p = 0.05 and p = 0.05, respectively). However, no significant correlations emerged between MSIs and depression or work-related factors. Conclusions: This study highlights the urgency of implementing proactive measures to prevent and manage MSDs within the nursing profession. Moreover, it emphasizes the critical need to enhance working conditions and provide robust support mechanisms to safeguard the mental health of nursing professionals.Open AccessOpen Access.

An Elastin-derived composite matrix for enhanced vascularized and innervated bone tissue reconstruction: from material development to preclinical evaluation.

Despite progress in bone tissue engineering, reconstruction of large bone defects remains an important clinical challenge. Here, we developed a biomaterial designed to recruit bone cells, endothelial cells, and neuronal fibers within the same matrix, enabling bone tissue regeneration. The bioactive matrix is based on modified elastin-like polypeptides (ELPs) grafted with laminin-derived adhesion peptides IKVAV and YIGSR, and the SNA15 peptide for retention of hydroxyapatite (HA) particles. The composite matrix shows suitable porosity, interconnectivity, biocompatibility for endothelial cells, and the ability to support neurites outgrowth by sensory neurons. Subcutaneous implantation led to the formation of osteoid tissue, characterized by the presence of bone cells, vascular networks, and neuronal structures, while minimizing inflammation. Using a rat femoral condyle defect model, we performed longitudinal micro-CT analysis, which demonstrates a significant increase in the volume of mineralized tissue when using the ELP-based matrix compared to empty defects and a commercially available control (Collapat). Furthermore, visible blood vessel networks and nerve fibers are observed within the lesions after a period of two weeks. By incorporating multiple key components that support cell growth, mineralization, and tissue integration, this ELP-based composite matrix provides a holistic and versatile solution to enhance bone tissue regeneration. This article is protected by copyright. All rights reserved.

Development of an innovative analytical method for forensic detection of cocaine, antidepressants, and metabolites in postmortem blood using magnetic nanoparticles.

Cocaine and antidepressants rank high globally in substance consumption, emphasizing their impact on public health. The determination of these compounds and related substances in biological samples is crucial for forensic toxicology. This study focused on developing an innovative analytical method for the determination of cocaine, antidepressants, and their related metabolites in postmortem blood samples, using unmodified commercial Fe3O4 nanoparticles as a sorbent for dispersive magnetic solid-phase extraction (m-d-SPE), coupled with liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis. An aliquot of 100 µL of whole blood and 5 µL of the internal standard pool were added to 30 mg of nanoparticles. The nanoparticles were separated from the sample using a neodymium magnet inserted into a 3D-printed microtube rack. The liquid was then discarded, followed by desorption with 300 µL of 1/1/1 acetonitrile/methanol/ethyl acetate. The sample was vortexed and separated, and 1.5 µL of the organic supernatant was injected into the LC-MS/MS. The method was acceptably validated and successfully applied to 263 postmortem blood samples. All samples evaluated in this study were positive for at least one substance. The most frequent analyte was benzoylecgonine, followed by cocaine and cocaethylene. The most common antidepressants encountered in the analyzed samples were citalopram and fluoxetine, followed by fluoxetine's metabolite norfluoxetine. This study describes the first report of this sorbent in postmortem blood analysis, demonstrating satisfactory results for linearity, precision, accuracy, and selectivity for all compounds. The method's applicability was confirmed, establishing it as an efficient and sustainable alternative to traditional techniques for forensic casework.

Embedded cyber-physical system for physiological control of ventricular assist devices

Ventricular Assist Devices (VADs) play a crucial role in both bridging to transplantation and serving as destination therapy for congestive heart failure (CHF) management. This study aims to address the limitations of existing control strategies for VADs, specifically their inability to adapt automatically to hemodynamic changes. It proposes a novel embedded cyber-physical system (CPS) based on real-time data processing, reconfigurable architecture, and communication protocols aligned with Health 4.0 concepts to enhance physiological control over VADs (PC-VAD). The research employs a multi-objective PC-VAD approach within a hybrid cardiovascular simulator. An embedded CPS is introduced to overcome challenges related to differences in controller characteristics between computers and embedded systems. The study assesses the performance of the embedded CPS by comparing it with a computer-based control system. The embedded CPS demonstrates outcomes comparable to the computer-based control system, maintaining mean arterial pressure and cardiac output at physiological levels. Even in the face of variations in ejection fraction, the embedded CPS dynamically adjusts the pump's rotational speed based on simulated clinical conditions. Notably, there is no aortic reflux to the ventricle through the VAD during testing. These findings affirm the satisfactory control performance of the embedded CPS in regulating VADs. The study concludes that the embedded CPS effectively addresses the limitations of current VAD control strategies, exhibiting control performance comparable to computer-based systems. However, further experimentation and in vivo studies are necessary to validate and ensure its applicability in real-world scenarios.

CD155/PVR determines acute myeloid leukemia targeting by Delta One T cells.

ABSTRACT: Relapsed or refractory acute myeloid leukemia (AML) remains a major therapeutic challenge. We have recently developed a Vδ1+ γδ T cell-based product for adoptive immunotherapy, named Delta One T (DOT) cells, and demonstrated their cytolytic capacity to eliminate AML cell lines and primary blasts in vitro and in vivo. However, the molecular mechanisms responsible for the broad DOT-cell recognition of AML cells remain poorly understood. Here, we dissected the role of natural killer (NK) cell receptor ligands in AML cell recognition by DOT cells. Screening of multiple AML cell lines highlighted a strong upregulation of the DNAM-1 ligands, CD155/pulmonary vascular resistance (PVR), CD112/nectin-2, as well as the NKp30 ligand, B7-H6, in contrast with NKG2D ligands. CRISPR-mediated ablation revealed key nonredundant and synergistic contributions of PVR and B7-H6 but not nectin-2 to DOT-cell targeting of AML cells. We further demonstrate that PVR and B7-H6 are critical for the formation of robust immunological synapses between AML and DOT cells. Importantly, PVR but not B7-H6 expression in primary AML samples predicted their elimination by DOT cells. These data provide new mechanistic insight into tumor targeting by DOT cells and suggest that assessing PVR expression levels may be highly relevant to DOT cell-based clinical trials.

Reliability of roadside oral fluid testing devices for ∆9 -tetrahydrocannabinol (∆9 -THC) detection.

Driving under the influence of cannabis (DUIC) is increasing worldwide, and cannabis is the most prevalent drug after alcohol in impaired driving cases, emphasizing the need for a reliable traffic enforcement strategy. ∆9 -tetrahydrocannabinol (THC) detection in oral fluid has great potential for identifying recent cannabis use; however, additional data are needed on the sensitivities, specificities, and efficiencies of different oral fluid devices for detecting cannabinoids at the roadside by police during routine traffic safety enforcement efforts. At the roadside, 8945 oral fluid THC screening tests were performed with four devices: AquilaScan®, Dräger DrugTest®, WipeAlyser Reader®, and Druglizer®. A total of 530 samples screened positive for THC (5.9%) and were analyzed by liquid chromatography-tandem mass spectrometry at multiple cutoff concentrations (2 ng/mL, 10 ng/mL, and manufacturers' recommended device cutoffs) to investigate device performance. Results varied substantially, with sensitivities of 0%-96.8%, specificities of 89.8%-98.5%, and efficiencies of 84.3%-97.8%. The Dräger DrugTest® outperformed the other devices with a 96.8% sensitivity, 97.1% specificity, and 97.0% efficiency at a 5-ng/mL LC-MS/MS confirmation cutoff. The WipeAlyser Reader® had good performance with a 91.4% sensitivity, 97.2% specificity, and 96.4% efficiency. AquilaScan® and Druglizer® had unacceptable performance for cannabinoid detection, highlighted by sensitivity <13%. The choice of roadside oral fluid testing device must offer good analytical performance for cannabinoids because of its high prevalence of use and impact on road safety.

Clinical, biochemical and histological features related to treatment response and prognosis in autoimmune hepatitis.

INTRODUCTION AND OBJECTIVES: Autoimmune hepatitis (AIH) is a rare disease with a complex and not fully understood pathogenesis. Prognostic factors that might influence treatment response, relapse rates, and transplant-free survival are not well established. This study investigates clinical and biochemical markers associated with response to immunosuppression in patients with AIH. MATERIALS AND METHODS: This retrospective cohort study included 101 patients with AIH treated with immunosuppressants and followed at the Federal University of Minas Gerais, Brazil, from 1990 to 2018. Pretreatment data such as clinical profiles, laboratory, and histological exams were analyzed regarding biochemical response at one year, histological remission, relapse, and death/transplantation rates. RESULTS: Cirrhosis was present in 59 % of cases at diagnosis. One-year biochemical remission was observed in 55.7 % of the patients and was found to be a protective factor for liver transplant. Overall survival was 89 %. Patients with ascites at disease onset showed a higher aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ratio and elevated Model of end-stage liver disease (MELD) score. The presence of ascites was significantly associated with a 20-fold increase in mortality rate. CONCLUSIONS: AIH has a severe clinical phenotype in Brazilians, with high rates of cirrhosis and low remission rates. Early diagnosis and treatment are essential for achieving remission and reducing complications. The presence of ascites is significantly associated with mortality, emphasizing the importance of monitoring and prompt intervention. This study also stresses the need for further research on AIH in Latin America.

Applications of Mass Spectrometry in the Characterization, Screening, Diagnosis, and Prognosis of COVID-19.

Mass spectrometry (MS) is a powerful analytical technique that plays a central role in modern protein analysis and the study of proteostasis. In the field of advanced molecular technologies, MS-based proteomics has become a cornerstone that is making a significant impact in the post-genomic era and as precision medicine moves from the research laboratory to clinical practice. The global dissemination of COVID-19 has spurred collective efforts to develop effective diagnostics, vaccines, and therapeutic interventions. This chapter highlights how MS seamlessly integrates with established methods such as RT-PCR and ELISA to improve viral identification and disease progression assessment. In particular, matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) takes the center stage, unraveling intricate details of SARS-CoV-2 proteins, revealing modifications such as glycosylation, and providing insights critical to formulating therapies and assessing prognosis. However, high-throughput analysis of MALDI data presents challenges in manual interpretation, which has driven the development of programmatic pipelines and specialized packages such as MALDIquant. As we move forward, it becomes clear that integrating proteomic data with various omic findings is an effective strategy to gain a comprehensive understanding of the intricate biology of COVID-19 and ultimately develop targeted therapeutic paradigms.

A validated dilute-and-shoot LC-MS/MS urine screening for the analysis of 95 illicit drugs and medicines: insights from clinical and forensic Brazilian cases.

Urine toxicological analysis is a relevant tool in both clinical and forensic scenarios, enabling the diagnosis of acute poisonings, elucidation of deaths, verification of substance use in the workplace, and identification of drug-facilitated crimes. For these analyses, the dilute-and-shoot technique associated with liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS) is a promising alternative since it has demonstrated satisfactory results and broad applicability. This study developed and validated a comprehensive LC-MS-MS screening method to analyze 95 illicit drugs and medicines in urine samples and application to clinical and forensic Brazilian cases. The dilute-and-shoot protocol was defined through multivariate optimization studies and was set using 100 µL of sample and 300 µL of solvent. The total chromatographic run time was 7.5 minutes. The method was validated following the recommendations of the ANSI/ASB Standard 036 Guideline. The lower limits of quantification varied from 20 to 100 ng/mL. Within-run and between-run precision CVs% were lower than 20%, and bias was within ± 20%. Only four of the 95 analytes presented significant ionization suppression or enhancement (> 25%). As proof of applicability, 839 urine samples from in vivo and postmortem cases were analyzed. In total, 90.9% of the analyzed samples were positive for at least one substance, and 78 of the 95 analytes were detected. The most prevalent substances were lidocaine (40.2%), acetaminophen (38.0%), and benzoylecgonine (31.5%). The developed method proved to be an efficient and simplified alternative for analyzing 95 therapeutic and illicit drugs in urine samples. Additionally, the results obtained from sample analysis are essential to understanding the profile of Brazilian substance use, serving as a valuable database for the promotion of health and safety public policies.

Tranexamic acid in bleeding reduction and operative time of nasal surgeries: systematic review and meta-analysis.

PURPOSE: Our study goal is to review the efficacy of tranexamic acid in reducing blood loss and operative time in nasal surgeries. METHODS: We included randomized clinical trials using oral or intravenous tranexamic acid, excluded non-randomized studies, topic administration, coagulopathy, and using other drugs interfering in the coagulation cascade. Online databases, National Library of Medicine (MEDLINE-PubMED), Latin American and Caribbean Literature on Health Sciences (Lilacs), Cochrane Library, Embase and Google Scholar were used to perform the search. The review was registered in PROSPERO by no CRD42022310977. Two authors, independently, selected the articles meeting the inclusion criteria. They extracted the data and used RevMan 5 software to perform the meta-analysis. RESULTS: Our search resulted in 16 RCTs that were included in the meta-analysis totalizing 1108 patients. Studies were evaluated resulting in a low risk of bias for the five domains. The use of tranexamic acid resulted in significant reduction in duration of surgery (DOS) and intraoperative blood loss (IBL) had significant reduction. The level of evidence according to GRADE System was high in all studies and variables. CONCLUSION: Tranexamic acid has an important role in reducing intraoperative blood loss and duration of surgery. Our study has some limitations due to the low number of RCTs available in the literature.

Adesão à técnica de higiene das mãos: estudo observacional / Adhesión a la técnica de higiene de manos: estudio observacional / Adherence to hand hygiene technique: an observational study

Resumo Objetivo Verificar a adesão e a qualidade da técnica de higiene das mãos realizada por profissionais de saúde nos momentos preconizados e identificar os fatores impactantes. Métodos Estudo observacional, com 41 profissionais de Unidade de Terapia Intensiva Adulto de um hospital de ensino brasileiro. A coleta de dados foi de setembro a dezembro de 2021, utilizando questionário sociodemográfico e formulário de observação da Organização Mundial da Saúde. Foram aplicados testes estatísticos de análise binomial e modelo de regressão logística de efeitos mistos e adotou-se nível de significância de 0,05. Resultados Um total de 1.055 oportunidades de Higiene das Mãos foram observadas, a taxa de adesão foi de 23,98% e pode-se verificar que os profissionais não executaram a técnica preconizada. O teste binomial verificou maior adesão aos momentos "após" quando comparados aos momentos "antes" (p< 0,001) e foi constatado impacto negativo do uso de luvas (p< 0,001). O modelo logístico reforçou a maior adesão nos momentos "após". Ainda que a adesão esteja baixa entre todas as categorias profissionais, o modelo logístico demonstrou mais chances de higiene das mãos pelos enfermeiros. Conclusão A adesão à higiene das mãos foi consideravelmente baixa principalmente considerando a técnica adequada. Foi verificado impacto negativo do uso de luvas na adesão higiene das mãos. Os profissionais demonstraram maiores chances de aderirem a higiene das mãos nos momentos "após" quando comparados aos momentos "antes".

Resumen Objetivo Verificar la adhesión y la calidad de la técnica de higiene de manos realizada por profesionales de la salud en los momentos recomendados e identificar los factores impactantes. Métodos Estudio observacional con 41 profesionales de una unidad de cuidados intensivos adulta de un hospital universitario brasileño. La recopilación de datos se realizó de septiembre a diciembre de 2021, mediante un cuestionario sociodemográfico y un formulario de observación de la Organización Mundial de la Salud. Se aplicaron pruebas estadísticas de análisis binominal y el modelo de regresión logística de efectos mixtos, y se adoptó un nivel de significación de 0,05. Resultados Se observó un total de 1.055 oportunidades de higiene de manos. El índice de adhesión fue del 23,98 % y se pudo verificar que los profesionales no ejecutan la técnica recomendada. La prueba binominal verificó una mayor adhesión en los momentos "después" comparado con los momentos "antes" (p<0,001) y se constató un impacto negativo del uso de guantes (p<0,001). El modelo logístico reforzó la mayor adhesión en los momentos "después". Aunque la adhesión sea baja en todas las categorías profesionales, el modelo logístico demostró mayor probabilidad de higiene de manos por parte de los enfermeros. Conclusión La adhesión a la higiene de manos fue considerablemente baja, sobre todo si se considera la técnica adecuada. Se verificó un impacto negativo del uso de guantes en la adhesión a la higiene de manos. Los profesionales demostraron mayores probabilidades de adhesión a la higiene de manos en los momentos "después" comparado con los momentos "antes".

Abstract Objective To verify adherence and quality of hand hygiene techniques performed by health professionals at recommended times and identify impacting factors. Methods This is an observational study, with 41 professionals from the Adult Intensive Care Unit of a Brazilian teaching hospital. Data collection took place from September to December 2021, using a sociodemographic questionnaire and observation form from the World Health Organization. Statistical tests of binomial analysis and mixed-effects logistic regression model were applied, and a significance level of 0.05 was adopted. Results A total of 1,055 hand hygiene opportunities were observed; the adherence rate was 23.98%; and it can be seen that professionals did not perform the recommended technique. The binomial test verified greater adherence to moments "after" when compared to moments "before" (p< 0.001) and a negative impact of using gloves was found (p< 0.001). The logistical model reinforced greater adherence in moments "after". Even though adherence is low among all professional categories, the logistical model demonstrated more chances of hand hygiene by nurses. Conclusion Adherence to hand hygiene was considerably low, especially considering the appropriate technique. A negative impact of using gloves on hand hygiene adherence was verified. Professionals demonstrated greater chances of adhering to hand hygiene in the moments "after" when compared to moments "before".

A Multi-objective Physiological Control for Continuous Flow Left Ventricular Assist Devices: Comparison of Estimator versus Sensor-based Feedback.

Left Ventricular Assist Devices have been successfully used for the treatment of Congestive Heart failure in patients who are not eligible for heart transplantation. This paper describes the implementation and comparison of the performance of a pressure sensor-based feedback controller. The strategies were tested on a mock loop of the systemic circulation. The results show that the use of pressure sensors generated a more accurate response of the controller compared to the use of estimators.Clinical Relevance- The study describes the integration of a LVAD physiological controller to a dynamic wireless monitoring system.

Photodynamic Therapy Directed to Melanoma Skin Cancer by Thermosensitive Hydrogel Containing Chlorophyll A.

Melanoma, a severe form of skin cancer intricately linked to genetic and environmental factors, is predicted to reach 100,000 new cases worldwide by 2040, underscoring the need for effective and safe treatment options. In this study, we assessed the efficacy of a photosensitizer called Chlorophyll A (Chl-A) incorporated into hydrogels (HGs) made of chitosan (CS) and poloxamer 407 (P407) for Photodynamic Therapy (PDT) against the murine melanoma cell line B16-F10. The HG was evaluated through various tests, including rheological studies, SEM, and ATR-FTIR, along with cell viability assays. The CS- and P407-based HGs effectively released Chl-A and possessed the necessary properties for topical application. The photodynamic activity of the HG containing Chl-A was evaluated in vitro, demonstrating high therapeutic potential, with an IC50 of 25.99 µM-an appealing result when compared to studies in the literature reporting an IC50 of 173.8 µM for cisplatin, used as a positive control drug. The developed formulation of CS and P407-based HG, serving as a thermosensitive system for topical applications, successfully controlled the release of Chl-A. In vitro cell studies associated with PDT exhibited potential against the melanoma cell line.

Therapeutic avenues for γδ T cells in cancer.

γδ T cells are regarded as promising effector lymphocytes for next-generation cancer immunotherapies. In spite of being relatively rare in human peripheral blood, γδ T cells are more abundant in epithelial tissues where many tumors develop, and have been shown to actively participate in anticancer immunity as cytotoxic cells or as "type 1" immune orchestrators. A major asset of γδ T cells for tackling advanced cancers is their independence from antigen presentation via the major histocompatibility complex, which clearly sets them apart from conventional αß T cells. Here we discuss the main therapeutic strategies based on human γδ T cells. These include antibody-based bispecific engagers and adoptive cell therapies, either focused on the Vδ1+ or Vδ2+ γδ T-cell subsets, which can be expanded selectively and differentiated or engineered to maximize their antitumor functions. We review the preclinical data that supports each of the therapeutic strategies under development; and summarize the clinical trials being pursued towards establishing γδ T cell-based treatments for solid and hematological malignancies.

Adaptive reinforcement learning for task scheduling in aircraft maintenance.

This paper proposes using reinforcement learning (RL) to schedule maintenance tasks, which can significantly reduce direct operating costs for airlines. The approach consists of a static algorithm for long-term scheduling and an adaptive algorithm for rescheduling based on new maintenance information. To assess the performance of both approaches, three key performance indicators (KPIs) are defined: Ground Time, representing the hours an aircraft spends on the ground; Time Slack, measuring the proximity of tasks to their due dates; and Change Score, quantifying the similarity level between initial and adapted maintenance plans when new information surfaces. The results demonstrate the efficacy of RL in producing efficient maintenance plans, with the algorithms complementing each other to form a solid foundation for routine tasks and real-time responsiveness to new information. While the static algorithm performs slightly better in terms of Ground Time and Time Slack, the adaptive algorithm excels overwhelmingly in terms of Change Score, offering greater flexibility in handling new maintenance information. The proposed RL-based approach can improve the efficiency of aircraft maintenance and has the potential for further research in this area.

FOXO family isoforms.

FOXO family of proteins are transcription factors involved in many physiological and pathological processes including cellular homeostasis, stem cell maintenance, cancer, metabolic, and cardiovascular diseases. Genetic evidence has been accumulating to suggest a prominent role of FOXOs in lifespan regulation in animal systems from hydra, C elegans, Drosophila, and mice. Together with the observation that FOXO3 is the second most replicated gene associated with extreme human longevity suggests that pharmacological targeting of FOXO proteins can be a promising approach to treat cancer and other age-related diseases and extend life and health span. However, due to the broad range of cellular functions of the FOXO family members FOXO1, 3, 4, and 6, isoform-specific targeting of FOXOs might lead to greater benefits and cause fewer side effects. Therefore, a deeper understanding of the common and specific features of these proteins as well as their redundant and specific functions in our cells represents the basis of specific targeting strategies. In this review, we provide an overview of the evolution, structure, function, and disease-relevance of each of the FOXO family members.