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    Priorities and Progress in Gram-positive Bacterial Infection Research by the Antibacterial Resistance Leadership Group: A Narrative Review
    (2023)
    Sarah B Doernberg
    ;
    Cesar A Arias
    ;
    Deena R Altman
    ;
    Ahmed Babiker
    ;
    Helen W Boucher
    <jats:title>Abstract</jats:title><jats:p>The Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, (2) determine the role of dalbavancin in MRSA bloodstream infection, (3) characterize enterococcal bloodstream infections, (4) demonstrate the benefits of short-course therapy for pediatric community-acquired pneumonia, (5) develop quality of life measures for use in clinical trials, and (6) advance understanding of the microbiome. Future studies will incorporate innovative methodologies with a focus on interventional clinical trials that have the potential to change clinical practice for difficult-to-treat infections, such as MRSA bloodstream infections.</jats:p>
      8Scopus© Citations 7
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    Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine
    (2023)
    Macarena Las Heras
    ;
    Benjamín Szenfeld
    ;
    Rami A. Ballout
    ;
    Emanuele Buratti
    ;
    Silvana Zanlungo
    <jats:title>Abstract</jats:title><jats:p>Niemann-Pick type C (NPC) disease is a lysosomal storage disease (LSD) characterized by the buildup of endo-lysosomal cholesterol and glycosphingolipids due to loss of function mutations in the <jats:italic>NPC1</jats:italic> and <jats:italic>NPC2</jats:italic> genes. NPC patients can present with a broad phenotypic spectrum, with differences at the age of onset, rate of progression, severity, organs involved, effects on the central nervous system, and even response to pharmacological treatments. This article reviews the phenotypic variation of NPC and discusses its possible causes, such as the remaining function of the defective protein, modifier genes, sex, environmental cues, and splicing factors, among others. We propose that these factors should be considered when designing or repurposing treatments for this disease. Despite its seeming complexity, this proposition is not far-fetched, considering the expanding interest in precision medicine and easier access to multi-omics technologies.</jats:p>
    Scopus© Citations 7  2
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    Patient and Carer Experiences with Bladder Cancer: Results from a Global Survey in 45 Countries
    (2023)
    Lydia E. Makaroff
    ;
    Alex Filicevas
    ;
    Shannon Boldon
    ;
    Patrick Hensley
    ;
    Peter C. Black
      7Scopus© Citations 8
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    Small molecules to perform big roles: The search for Parkinson's and Huntington's disease therapeutics
    (2023)
    Rodrigo Pérez-Arancibia
    ;
    Marisol Cisternas-Olmedo
    ;
    Denisse Sepúlveda
    ;
    Paulina Troncoso-Escudero
    ;
    Rene L. Vidal
    <jats:p>Neurological motor disorders (NMDs) such as Parkinson's disease and Huntington's disease are characterized by the accumulation and aggregation of misfolded proteins that trigger cell death of specific neuronal populations in the central nervous system. Differential neuronal loss initiates the impaired motor control and cognitive function in the affected patients. Although major advances have been carried out to understand the molecular basis of these diseases, to date there are no treatments that can prevent, cure, or significantly delay the progression of the disease. In this context, strategies such as gene editing, cellular therapy, among others, have gained attention as they effectively reduce the load of toxic protein aggregates in different models of neurodegeneration. Nevertheless, these strategies are expensive and difficult to deliver into the patients' nervous system. Thus, small molecules and natural products that reduce protein aggregation levels are highly sought after. Numerous drug discovery efforts have analyzed large libraries of synthetic compounds for the treatment of different NMDs, with a few candidates reaching clinical trials. Moreover, the recognition of new druggable targets for NMDs has allowed the discovery of new small molecules that have demonstrated their efficacy in pre-clinical studies. It is also important to recognize the contribution of natural products to the discovery of new candidates that can prevent or cure NMDs. Additionally, the repurposing of drugs for the treatment of NMDs has gained huge attention as they have already been through clinical trials confirming their safety in humans, which can accelerate the development of new treatment. In this review, we will focus on the new advances in the discovery of small molecules for the treatment of Parkinson's and Huntington's disease. We will begin by discussing the available pharmacological treatments to modulate the progression of neurodegeneration and to alleviate the motor symptoms in these diseases. Then, we will analyze those small molecules that have reached or are currently under clinical trials, including natural products and repurposed drugs.</jats:p>
      3Scopus© Citations 21
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      44  1Scopus© Citations 38
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    Dementia in Latin America: Paving the way toward a regional action plan
    (2020)
    Mario Alfredo Parra
    ;
    Sandra Baez
    ;
    Lucas Sedeño
    ;
    Cecilia Gonzalez Campo
    ;
    Hernando Santamaría‐García
      2Scopus© Citations 115
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    The Impact of a Yoga-Based Mindfulness Intervention versus Psycho-Educational Session for Older Adults with Mild Cognitive Impairment: The Protocol of a Randomized Controlled Trial
    (2022)
    Maryam Farhang
    ;
    Graciela Rojas
    ;
    Pablo Martínez
    ;
    BEHRENS PELLEGRINO, MARIA ISABEL  
    ;
    Álvaro I. Langer
    <jats:p>Background: There is a global agreement in the medical community that a significant proportion of dementia cases could be prevented or postponed. One of the factors behind this agreement comes from scientific evidence showing that mind-body interventions such as mindfulness and yoga for the elderly have been related to a range of positive outcomes, including improved cognition performance in seniors with mild cognitive impairment (MCI). Objective: This study aims to evaluate the effectiveness of a yoga-based mindfulness intervention (YBM) versus psychoeducational sessions for older adults with MCI attending Hospital Clinic Universidad de Chile in Santiago. Method: Two-arm, individually randomized controlled trial (RCT) will be carried out at Clinical Hospital Universidad de Chile in Santiago. Older people over 60 years with any type of MCI using a score &lt; 21 in the Montreal Cognitive Assessment (MoCA) test and a score of 0.05 in the Clinical Dementia Rating (CDR) Scale; and with preserved activities of daily living will be randomly assigned with an allocation ratio of 1:1 in either the yoga-based mindfulness intervention or the active control group based on the psycho-educational program. People who have performed yoga and/or mindfulness in the last 6 months or/and people with a psychiatric clinical diagnosis will be excluded from the study. Montreal Cognitive Assessment, the Lawton Instrumental Activities of Daily Living Scale (IADL), the Barthel Index (BI), the Pemberton happiness index, the Geriatric Anxiety Inventory (GAI) as well as the Geriatric Depression Scale (GDS-5) will be administered by blinded outcomes assessors before random assignment (Pre-test), the week following the last session of the intervention (post-test), and then after 3- and 6-months follow-up. Results: The YBM intervention protocol based on a video recording has been adapted and designed. This is the first RCT to examine the effects of a yoga-based mindfulness intervention in improving cognitive and physical functions and mental health outcomes for Chilean elderly diagnosed with MCI. It is expected to be implemented as an acceptable and effective non-pharmacological option for older people with MCI. Conclusion: Providing evidence-based programs such as preventive therapy for Alzheimer’s disease has relevant implications for public mental health services in Chile.</jats:p>
    Scopus© Citations 7  1
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    MET Signaling Pathways, Resistance Mechanisms, and Opportunities for Target Therapies
    (2022)
    RIVAS VERA, SOLANGE VERÓNICA  
    ;
    Arnaldo Marín
    ;
    Suraj Samtani
    ;
    Evelin González-Feliú
    ;
    ARMISEN YAÑEZ, RICARDO AMADO  
    <jats:p>The MET gene, known as MET proto-oncogene receptor tyrosine kinase, was first identified to induce tumor cell migration, invasion, and proliferation/survival through canonical RAS-CDC42-PAK-Rho kinase, RAS-MAPK, PI3K-AKT-mTOR, and β-catenin signaling pathways, and its driver mutations, such as MET gene amplification (METamp) and the exon 14 skipping alterations (METex14), activate cell transformation, cancer progression, and worse patient prognosis, principally in lung cancer through the overactivation of their own oncogenic and MET parallel signaling pathways. Because of this, MET driver alterations have become of interest in lung adenocarcinomas since the FDA approval of target therapies for METamp and METex14 in 2020. However, after using MET target therapies, tumor cells develop adaptative changes, favoring tumor resistance to drugs, the main current challenge to precision medicine. Here, we review a link between the resistance mechanism and MET signaling pathways, which is not only limited to MET. The resistance impacts MET parallel tyrosine kinase receptors and signals shared hubs. Therefore, this information could be relevant in the patient’s mutational profile evaluation before the first target therapy prescription and follow-up to reduce the risk of drug resistance. However, to develop a resistance mechanism to a MET inhibitor, patients must have access to the drugs. For instance, none of the FDA approved MET inhibitors are registered as such in Chile and other developing countries. Constant cross-feeding between basic and clinical research will thus be required to meet future challenges imposed by the acquired resistance to targeted therapies.</jats:p>
    Scopus© Citations 15  16
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    Settings and monitoring of mechanical ventilation during physical therapy in adult critically ill patients: protocol for a scoping review
    (2019)
    GONZALEZ SEGUEL, FELIPE ANDRES  
    ;
    CAMUS MOLINA, AGUSTIN  
    ;
    Anita Jasmén Sepúlveda
    ;
    PEREZ ARAOS, RODRIGO ALEJANDRO  
    ;
    Jorge Molina Blamey
    <jats:sec><jats:title>Introduction</jats:title><jats:p>Early mobilisation has been extensively advocated to improve functional outcomes in critically ill patients, even though consistent evidence of its benefits has remained elusive. These conflicting results could be explained by a lack of knowledge on the optimal dosage of physical therapy and a mismatch between ventilatory support and exercise-induced patient ventilatory demand. Modern mechanical ventilators provide real-time monitoring of respiratory/metabolic variables and ventilatory setting that could be used for physical therapy dosage or ventilatory support titration, allowing individualised interventions in these patients. The aim of this review is to comprehensively map and summarise current knowledge on adjustments of respiratory support and respiratory or metabolic monitoring during physical therapy in adult critically ill mechanically ventilated patients.</jats:p></jats:sec><jats:sec><jats:title>Methods and analysis</jats:title><jats:p>This is a scoping review protocol based on the methodology of the Joanna-Briggs-Institute. The search strategy will be conducted from inception to 30 June 2019 as a cut-off date in PubMed, CINAHL, Rehabilitation &amp; Sport Medicine, Scielo Citation Index, Epistemónikos, Clinical Trials, PEDro and Cochrane Library, performed by a biomedical librarian and two critical care physiotherapists. All types of articles will be selected, including conference abstracts, clinical practice guidelines and expert recommendations. Bibliometric variables, patient characteristics, physical therapy interventions, ventilator settings and respiratory or metabolic monitoring will be extracted. The identified literature will be analysed by four critical care physiotherapists and reviewed by a senior critical care physician.</jats:p></jats:sec><jats:sec><jats:title>Ethics and dissemination</jats:title><jats:p>Ethical approval is not required. The knowledge-translation of the results will be carried out based on the End-of-Grant strategies: diffusion, dissemination and application. The results will be published in a peer-review journal, presentations will be disseminated in relevant congresses, and recommendations based on the results will be developed through training for mechanical ventilation and physical therapy stakeholders.</jats:p></jats:sec>
      5  1Scopus© Citations 5