Delacruzwilkinson3638
Pulmonary exacerbations (PExs) are significant life events in people with cystic fibrosis (CF), associated with declining lung function, reduced quality of life, hospitalizations, and decreased survival. The adult CF population is increasing worldwide, with many patients surviving prolonged periods with severe multimorbid disease. In many countries, the number of adults with CF exceeds the number of children, and PExs are particularly burdensome for adults as they tend to require longer courses and more IV treatment than children. The approach to managing PExs is multifactorial and needs to evolve to reflect this changing adult population. This review discusses PEx definitions, precipitants, treatments, and the wider implications to health-care resources. It reviews current management strategies, their relevance in particular to adults with CF, and highlights some of the gaps in our knowledge. A number of studies are underway to try to answer some of the unmet needs, such as the optimal length of treatment and the use of nonantimicrobial agents alongside antibiotics. An overview of these issues is provided, concluding that with the changing landscape of adult CF care, the definitions and management of PExs may need to evolve to enable continued improvements in outcomes across the age spectrum of CF.
Invasive mechanical ventilation is often initiated in the ED, and mechanically ventilated patients may be kept in the ED for hours before ICU transfer. Although lung-protective ventilation is beneficial, particularly in ARDS, it remains uncertain how often lung-protective tidal volumes are used in the ED, and whether lung-protective ventilation in this setting impacts patient outcomes.
What is the association between the use of lung-protective ventilation in the ED and outcomes among invasively ventilated patients?
A retrospective analysis (2011-2017) of a prospective registry from eight EDs enrolling consecutive adult patients (≥ 18 years) who received invasive mechanical ventilation in the ED was performed. Lung-protective ventilation was defined by use of tidal volumes≤ 8mL/kg predicted body weight. The primary outcome was hospital mortality. Secondary outcomes included development of ARDS, hospital length of stay, and total hospital costs.
The study included 4,174 patients, of whom 2,437 (58.4%) rem-centered outcomes, including lower hospital mortality, decreased incidence of ARDS, lower hospital length of stay, and decreased total costs. Protocol development promoting the regular use of lung-protective ventilation in the ED may be of value.
Therapeutic options for advanced neuroendocrine tumours (NETs) are limited. We investigated the efficacy and safety of surufatinib (HMPL-012, sulfatinib) in patients with extrapancreatic NETs.
SANET-ep was a randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 24 hospitals across China. Patients (aged 18 years or older) with unresectable or metastatic, well differentiated, extrapancreatic NETs, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression on no more than two types of previous systemic regimens were enrolled. Patients were centrally randomly assigned (21) using stratified block randomisation (block size 3) via an interactive web response system to receive oral surufatinib at 300 mg per day or matching placebo. Randomisation was stratified by tumour origin, pathological grade, and previous treatment. Patients, investigators, research staff and the sponsor study team were masked to treatment allocation. Crossover to the surufatinib group was alison MediPharma.
Hutchison MediPharma.
Surufatinib showed superior efficacy in extrapancreatic neuroendocrine tumours (NETs) in the phase 3 SANET-ep study. In SANET-p, we aimed to assess the efficacy and safety of surufatinib in patients with advanced pancreatic NETs.
SANET-p was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, done in 21 hospitals across China. Eligible patients were adults (aged 18 years or older) with progressive, advanced, well differentiated pancreatic NETs, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and progression on up to two kinds of previous systemic regimens for advanced disease. Patients were randomly assigned (21) via an interactive web response system to receive 300 mg of surufatinib or placebo, taken orally once per day in consecutive 4-week treatment cycles until disease progression, intolerable toxicity, withdrawal of consent, poor compliance, use of other antitumour medication, pregnancy, loss to follow-up, or if the investigator deemed discontinuation iOne on-treatment death in the placebo group was attributed to disease progression.
Surufatinib significantly improves progression-free survival and has an acceptable safety profile in patients with progressive, advanced pancreatic NETs, and could be a potential treatment option in this patient population.
Hutchison MediPharma.
Hutchison MediPharma.Recognizing a need for more guidance on the coronavirus disease 2019 (COVID-19) pandemic, members of the Archives of Physical Medicine and Rehabilitation Editorial Board invited several clinicians with early experience managing the disease to collaborate on a document to help guide rehabilitation clinicians in the community. This consensus document is written in a "question and answer" format and contains information on the following items common manifestations of the disease; rehabilitation recommendations in the acute hospital setting, recommendations for inpatient rehabilitation and special considerations. These suggestions are intended for use by rehabilitation clinicians in the inpatient setting caring for patients with confirmed or suspected COVID-19. The text represents the authors' best judgment at the time it was written. However, our knowledge of COVID-19 is growing rapidly. The reader should take advantage of the most up-to-date information when making clinical decisions.
To describe how different key stakeholders (i.e., interprofessional clinical care team and patients) perceive their role in promoting in-hospital mobility by systematically synthesizing qualitative literature.
PubMed, Ovid Medline, Ovid PsychInfo, and CINAHL were searched using terms relevant to mobility, hospitalization and qualitative research. 510 unique articles were retrieved and screened for eligibility.
Eligible qualitative studies included stakeholder perspectives on in-hospital mobility, including patients, nursing staff, rehabilitation staff, and physicians. Eleven articles remained after inclusion/exclusion criteria were applied.
At least two authors independently read, coded, and derived themes from each study. We used a team-based inductive approach to thematic synthesis informed by critical realism and the socioecological model. Reciprocal translation unified convergent and divergent constructs across primary studies. Investigator triangulation enhanced interpretation DATA SYNTHESIS. Thrshould take a systems approach and consider allocation of resources, clarity around professional responsibilities, and elevating patient and clinician expectations surrounding mobility.Genetic aberrations of the UBE3A gene encoding the E3 ubiquitin ligase E6AP underlie the development of Angelman syndrome (AS). Approximately 10% of AS individuals harbor UBE3A genes with point mutations, frequently resulting in the expression of full-length E6AP variants with defective E3 activity. Since E6AP exists in two states, an inactive and an active one, we hypothesized that distinct small molecules can stabilize the active state and that such molecules may rescue the E3 activity of AS-derived E6AP variants. Therefore, we established an assay that allows identifying modulators of E6AP in a high-throughput format. We identified several compounds that not only stimulate wild-type E6AP but also rescue the E3 activity of certain E6AP variants. Moreover, by chemical cross-linking coupled to mass spectrometry we provide evidence that the compounds stabilize an active conformation of E6AP. Thus, these compounds represent potential lead structures for the design of drugs for AS treatment.MYC is a major oncogenic transcriptional driver of most human cancers that has remained intractable to direct targeting because much of MYC is intrinsically disordered. Here, we have performed a cysteine-reactive covalent ligand screen to identify compounds that could disrupt the binding of MYC to its DNA consensus sequence in vitro and also impair MYC transcriptional activity in situ in cells. We have identified a covalent ligand, EN4, that targets cysteine 171 of MYC within a predicted intrinsically disordered region of the protein. We show that EN4 directly targets MYC in cells, reduces MYC and MAX thermal stability, inhibits MYC transcriptional activity, downregulates multiple MYC transcriptional targets, and impairs tumorigenesis. We also show initial structure-activity relationships of EN4 and identify compounds that show improved potency. Overall, we identify a unique ligandable site within an intrinsically disordered region of MYC that leads to inhibition of MYC transcriptional activity.A major portion of individuals affected by traumatic spinal cord injury (SCI) experience one or more types of chronic neuropathic pain (NP), which is often intractable to currently available treatments. The availability of reliable behavioral assays in pre-clinical models of SCI-induced NP is therefore critical to assess the efficacy of new potential therapies. Commonly used assays to evaluate NP-related behavior in rodents, such as Hargreaves thermal and von Frey mechanical testing, rely on the withdrawal response to an evoked stimulus. However, other assays that test spontaneous/non-evoked NP-related behavior or supraspinal aspects of NP would be highly useful for a more comprehensive assessment of NP following SCI. The Mouse Grimace Scale (MGS) is a tool to assess spontaneous, supraspinal pain-like behaviors in mice; however, the assay has not been characterized in a mouse model of SCI-induced chronic NP, despite the critical importance of mouse genetics as an experimental tool. We found that beginning 2 weeks after cervical contusion, SCI mice exhibited increased facial grimace features compared to laminectomy-only control mice, and this grimace phenotype persisted to the chronic time point of 5 weeks post-injury. We also found a significant relationship between facial grimace score and the evoked forepaw withdrawal response in both the Hargreaves and von Frey tests at 5 weeks post-injury when both laminectomy-only and SCI mice were included in the analysis. However, within only the SCI group, there was no correlation between grimace score and Hargreaves or von Frey responses. check details These results indicate both that facial grimace analysis can be used as an assay of spontaneous NP-related behavior in the mouse model of SCI and that the information provided by the MGS may be different than that provided by evoked tests of sensory function.The interaction of three proteins, viz. Bovine Serum Albumin (BSA), Human Serum Albumin (HSA) and Hen Egg White Lysozyme (HEWL) with gold nanoparticles (GNPs) is investigated using surface plasmon resonance (SPR) spectroscopy, fluorescence spectroscopy and circular dichroism (CD). Size and morphology of the samples was established using Transmission Electron Microscopy (TEM) and stability studies was established using zeta potential analysis. The stability of protein-GNP complex was found to be greater than that of individual protein as well as individual GNPs. Also HEWL-GNP complex was more stable compared to the other protein complexes. Absorbance of proteins increases with increase in gold nanoparticle concentration due to the extension of peptide strands of protein and decrease in hydrophobicity of gold nanoparticles. A ground state complex is also formed which is evident from the moderate shift observed in the absorbance peaks. Apparent association constant was also determined from the absorption spectra and was found to be maximum for HEWL and minimum for HSA.
