Lipid-lowering therapy with PCSK9-inhibitors in the management of cardiovascular high-risk patients: Effectiveness, therapy adherence and safety in a real world cohort

  Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9)-inhibitors have shown great po­tential in efficient lipid lowering to achieve low-density lipoprotein-cholesterol (LDL-C) treatment goals. The aim of the study was too describe the clinical use of PCSK9-inhibitors and to investigate therapy adherence and safety outside of clinical trials. Methods: Thirty-eight patients were treated with PSCK9-inhibitors. Patients were eligible for this therapy based on their individual cardiovascular risk and when all other available lipid-lowering regi­men had failed. Every patient answered a questionnaire concerning medical history and relevant side effects and therapy adherence. Results: Conventional therapy reduced patient LDL-C levels by about 38%. However, in 26 of the 38 patients, LDL-C treatment goals were not fulfilled because patients did not tolerate further dose es­calation due to side effects. Using a PCSK9 inhibitor, LDL-C levels were reduced by another 54% and 42% of patients reaching treatment goals. The results show that most patients still require concomitant therapy to reach LDL-C target levels. Three patients required dose reduction or change of the PCSK9 inhibitor. 16% did not inject the PCSK9 inhibitor regularly. Conclusions: Only a minority of patients reached the recommended LDL-C goals. PCSK9-inhibitors were generally well tolerated. Despite low rates of reported side effects, therapy adherence was incom­plete, with 6 patients not injecting PCSK9-inhibitors on a regular basis. In-depth information about the medication and close supervision is advisable. PCSK9 inhibitors have shown great potential in aggressive lipid lowering therapy, but basic therapy is still required in most cases. Close supervision is recommended to improve therapy adherence. (Cardiol J 2018; 25, 1: 32–41

Application of fragment-based methods for the development of Pseudomonas aeruginosa anti-virulence compounds

Pseudomonas aeruginosa is the cause of nosocomial infections and recurrent pneumonia in cystic fibrosis patients. Antibiotic treatment becomes increasingly difficult due to the spreading of multi-drug resistant strains and its ability to grow in a biofilm. The virulence of this pathogen is mainly controlled by quorum sensing (QS) systems. This process enables bacteria to coordinate the expression of virulence factors and biofilm formation as a function of cell density. For this purpose, P. aeruginosa utilize among others the pqs (Pseudomonas Quinolone Signal) system. In this study anti-virulence agents were developed interfering with the pqs system. During a fragment-based drug discovery campaign antagonists of the Pseudomonas Quinolone Signal Receptor (PqsR) were synthesized. Based on hits identified in a surface plasmon resonance (SPR) screening, novel lead structures were generated. This development process involved selective synthetic modifications of the hit structures and structure-based design methods. Fragments were successfully merged with moieties of an alternative compound class. The optimized structures displayed potent reduction of virulence factors and signaling molecules in P. aeruginosa. During another fragment screening the first synthetic PqsE ligands were identified. The binding mode of these fragments was elucidated. Furthermore, it was shown that the inhibition of the enzymatic activity did not translate into an effect on its virulence regulatory role.Pseudomonas aeruginsa ist ein Erreger nosokomialer Infektionen sowie von Pneumonien bei Patienten mit zystischer Fibrose. Die Antibiotikatherapie wird durch das vermehrte Auftreten von multiresistenten Stämmen und die Ausbildung von Biofilmen erschwert. Die Virulenz des Erregers wird hauptsächlich durch Quorum Sensing reguliert. Dies ermöglicht es dem Bakterium die Bildung von Virulenzfaktoren und Biofilmen in Abhängigkeit von der Zelldichte zu koordinieren. P. aeruginosa nutzt hierfür unter anderem das pqs (Pseudomonas Quinolone Signal) System. In dieser Arbeit wurden Substanzen entwickelt, die in dieses System eingreifen. Zunächst wurden in einem Fragment-basiertem Ansatz PqsR Antagonisten synthetisiert. Ausgehend von Fragmenten, die einem Surface Plasmon Resonance (SPR) Screening gefunden wurden, konnten neue Leitstrukturen generiert werden. Dies gelang durch gezielte synthetische Modifikation der Ausgangsverbindungen und dem Einsatz Struktur-basierter Methoden. Weiterhin konnten Fragmente mit Motiven aus einer anderen Strukturklasse erfolgreich kombiniert werden. Die optimierten Strukturen zeigten eine potente Absenkung der Virulenz und der Produktion von Signalmolekülen in P. aeruginosa. In einem weiteren Fragment Screening wurden die ersten synthetischen PqsE Liganden identifiziert und ihr Bindungsmodus aufgeklärt. Weiterhin konnte gezeigt werden, dass eine Inhibition der enzymatischen Funktion keinen Einfluss auf die Virulenz Regulation durch PqsE hat

Safety Recommendations for Evaluation and Surgery of the Head and Neck During the COVID-19 Pandemic

Importance The rapidly expanding novel coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, has challenged the medical community to an unprecedented degree. Physicians and health care workers are at added risk of exposure and infection during the course of patient care. Because of the rapid spread of this disease through respiratory droplets, health care workers who come in close contact with the upper aerodigestive tract during diagnostic and therapeutic procedures, such as otolaryngologists–head and neck surgeons, are particularly at risk. A set of safety recommendations was created based on a review of the literature and communications with physicians with firsthand knowledge of safety procedures during the COVID-19 pandemic. Observations A high number of health care workers were infected during the first phase of the pandemic in the city of Wuhan, China. Subsequently, by adopting strict safety precautions, other regions were able to achieve high levels of safety for health care workers without jeopardizing the care of patients. The most common procedures related to the examination and treatment of upper aerodigestive tract diseases were reviewed. Each category was reviewed based on the potential risk imposed to health care workers. Specific recommendations were made based on the literature, when available, or consensus best practices. Specific safety recommendations were made for performing tracheostomy in patients with COVID-19. Conclusions and Relevance Preserving a highly skilled health care workforce is a top priority for any community and health care system. Based on the experience of health care systems in Asia and Europe, by following strict safety guidelines, the risk of exposure and infection of health care workers could be greatly reduced while providing high levels of care. The provided recommendations, which may evolve over time, could be used as broad guidance for all health care workers who are involved in the care of patients with COVID-19

Handwerkliches Lackieren mit Virtual Reality (HandLeVR)

Kompetenzentwicklung in der beruflichen Aus- und Weiterbildung beinhaltet den Erwerb von Wissen, Fertigkeiten und Einstellungen, häufig mit einem Schwerpunkt auf psychomotorischer Koordination. Der Kompetenzerwerb in der Ausbildung zum Fahrzeuglackierer bzw. zur Fahrzeuglackiererin wird durch soziale, wirtschaftliche und ökologische Faktoren behindert. Um diese Hürden zu überwinden, entwickelt das Forschungsprojekt HandLeVR (Handlungsorientiertes Lernen in der VR-Lackierwerkstatt) ein Virtual-Reality-Training auf der Grundlage des empirisch validierten 4C/ID-Modells. Der Artikel stellt das Vorgehen und die Resultate des Projekts vor und präsentiert Ergebnisse einer ersten Evaluierungsstudie (z. B. zu Akzeptanz und Präsenzerleben)

Functional Identification of Tumor Suppressor Genes Through an in vivo RNA Interference Screen in a Mouse Lymphoma Model

2010 April 6Short hairpin RNAs (shRNAs) capable of stably suppressing gene function by RNA interference (RNAi) can mimic tumor-suppressor-gene loss in mice. By selecting for shRNAs capable of accelerating lymphomagenesis in a well-characterized mouse lymphoma model, we identified over ten candidate tumor suppressors, including Sfrp1, Numb, Mek1, and Angiopoietin 2. Several components of the DNA damage response machinery were also identified, including Rad17, which acts as a haploinsufficient tumor suppressor that responds to oncogenic stress and whose loss is associated with poor prognosis in human patients. Our results emphasize the utility of in vivo RNAi screens, identify and validate a diverse set of tumor suppressors, and have therapeutic implications

Effect of smoke on subcanopy shaded light, canopy temperature, and carbon dioxide uptake in an Amazon rainforest

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95278/1/gbc1694.pd

In Vivo RNAi Screening Identifies Regulators of Actin Dynamics as Key Determinants of Lymphoma Progression

April 1, 2010Mouse models have markedly improved our understanding of cancer development and tumor biology. However, these models have shown limited efficacy as tractable systems for unbiased genetic experimentation. Here, we report the adaptation of loss-of-function screening to mouse models of cancer. Specifically, we have been able to introduce a library of shRNAs into individual mice using transplantable Eμ-myc lymphoma cells. This approach has allowed us to screen nearly 1,000 genetic alterations in the context of a single tumor-bearing mouse. These experiments have identified a central role for regulators of actin dynamics and cell motility in lymphoma cell homeostasis in vivo. Validation experiments confirmed that these proteins represent bona fide lymphoma drug targets. Additionally, suppression of two of these targets, Rac2 and twinfilin, potentiated the action of the front-line chemotherapeutic vincristine, suggesting a critical relationship between cell motility and tumor relapse in hematopoietic malignancies.National Institutes of Health (U.S.) (RO1 CA128803-01)Massachusetts Institute of Technology. Dept. of Biology (Training Grant)Massachusetts Institute of Technology. Undergraduate Research Opportunities ProgramNational Cancer Institute (U.S.). Integrative Cancer Biology Program (Grant 1-U54-CA112967

Skill metrics for confronting global upper ocean ecosystem-biogeochemistry models against field and remote sensing data

Author Posting. © Elsevier B.V., 2009. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Journal of Marine Systems 76 (2009): 95-112, doi:10.1016/j.jmarsys.2008.05.015.We present a generalized framework for assessing the skill of global upper ocean ecosystem-biogeochemical models against in-situ field data and satellite observations. We illustrate the approach utilizing a multi-decade (1979-2004) hindcast experiment conducted with the Community Climate System Model (CCSM-3) ocean carbon model. The CCSM-3 ocean carbon model incorporates a multi-nutrient, multi-phytoplankton functional group ecosystem module coupled with a carbon, oxygen, nitrogen, phosphorus, silicon, and iron biogeochemistry module embedded in a global, threedimensional ocean general circulation model. The model is forced with physical climate forcing from atmospheric reanalysis and satellite data products and time-varying atmospheric dust deposition. Data-based skill metrics are used to evaluate the simulated time-mean spatial patterns, seasonal cycle amplitude and phase, and subannual to interannual variability. Evaluation data include: sea surface temperature and mixed layer depth; satellite derived surface ocean chlorophyll, primary productivity, phytoplankton growth rate and carbon biomass; large-scale climatologies of surface nutrients, pCO2, and air-sea CO2 and O2 flux; and time-series data from the Joint Global Ocean Flux Study (JGOFS). Where the data is sufficient, we construct quantitative skill metrics using: model-data residuals, time-space correlation, root mean square error, and Taylor diagrams.This work was supported in part by grants from the NSF/ONR National Ocean Partnership Program (N000140210370), the NASA Ocean Biology and Biogeochemistry Program (NNX07AL80G), and the NSF Center for Microbial Oceanography Research and Education (C-MORE)

Multi-Institutional Study Validates Safety of Intraoperative Cesium-131 Brachytherapy for Treatment of Recurrent Head and Neck Cancer

Introduction: Surgery is the primary treatment for resectable, non-metastatic recurrent head and neck squamous cell carcinoma (HNSCC). We explore the safety and oncologic benefit of intraoperative Cesium-131 (Cs-131) brachytherapy combined with salvage local and/or regional surgical resection. Methods and materials: Findings were reported from a single arm multi-institutional prospective phase 1/2 trial involving surgery plus Cs-131 (surgery + Cs-131) treatment. The results of two retrospective cohorts-surgery alone and surgery plus intensity modulated radiation therapy (surgery + ReIMRT)-were also described. Included patients had recurrent HNSCC and radiation history. Safety, tumor re-occurrence, and survival were evaluated. Results: Forty-nine patients were enrolled in the surgery + Cs-131 prospective study. Grade 1 to 3 adverse events (AEs) occurred in 18 patients (37%), and grade 4 AEs occurred in 2 patients. Postoperative percutaneous endoscopic gastrostomy (PEG) tubes were needed in 10 surgery + Cs-131 patients (20%), and wound and vascular complications were observed in 12 patients (24%). No cases of osteoradionecrosis were reported in the surgery + Cs-131 cohort. We found a 49% 2-year disease-free survival at the site of treatment with a substantial number of patients (31%) developing metastatic disease, which led to a 31% overall survival at 5 years. Conclusions: Among patients with local/regional recurrent HNSCC status-post radiation, surgery + Cs-131 demonstrated acceptable safety with compelling oncologic outcomes, as compared to historic control cohorts. Clinical trial registration: ClinicalTrials.gov, identifiers NCT02794675 and NCT02467738