No abstract

Transcribed from the SOST gene, sclerostin is an osteocyte-derived negative regulator of bone formation that inhibits osteoblastogenesis via antagonism of the Wnt pathway. Sclerostin is a promising therapeutic target for low bone mass diseases and neutralizing antibody therapies that target sclerostin are in development. Diverse stimuli regulate SOST including the vitamin D hormone, forskolin (Fsk), bone morphogenic protein 2 (BMP-2), oncostatin M (OSM), dexamethasone (Dex), and transforming growth factor (TGF)β1. To explore the mechanisms by which these compounds regulate SOST expression, we examined their ability to regulate a SOST reporter minigene containing the entire SOST locus or mutant minigene containing a deletion of the −1 kb to −2 kb promoter proximal region (−1 kb), ECR2, ECR5, or two point mutations in the MEF2 binding site of ECR5 (ECR5/MEF2). Previous reports suggest that both the PTH and TGFβ1 effects on SOST are mediated through ECR5 and that the action of PTH is mediated specifically via the MEF2 binding site at ECR5. Consistent with these reports, the suppressive effects of Fsk were abrogated following both ECR5 deletion and ECR5/MEF2 mutation. In contrast, we found that TGFβ1 negatively regulated SOST and that neither ECR5 nor ECR5/MEF2 was involved. Surprisingly, none of these four deletions/mutations abrogated the suppressive effects of the vitamin D hormone, OSM, Dex, or TGFβ1, or the positive effects of BMP-2. These data suggest that we need to move beyond ECR5 to understand SOST regulation.

Introduction: Among critically ill patients undergoing orotracheal intubation in the emergency department (ED) or intensive care unit (ICU), failure to visualize the vocal cords and intubate the trachea on the first attempt is associated with an increased risk of complications. Two types of laryngoscopes are commonly available: direct laryngoscopes and video laryngoscopes. For critically ill adults undergoing emergency tracheal intubation, it remains uncertain whether use of a video laryngoscope increases the incidence of successful intubation on the first attempt compared with use of a direct laryngoscope. Methods and Analysis: The DirEct Versus VIdeo LaryngosCopE (DEVICE) trial is a prospective, multi-center, non-blinded, randomized trial being conducted in 6 EDs and 10 ICUs in the United States. The trial plans to enroll up to 2,000 critically ill adults undergoing orotracheal intubation with a laryngoscope. Eligible patients are randomized 1:1 to the use of a video laryngoscope or a direct laryngoscope for the first intubation attempt. The primary outcome is successful intubation on the first attempt. The secondary outcome is the incidence of severe complications between induction and 2 minutes after intubation, defined as the occurrence of one or more of the following: severe hypoxemia (lowest oxygen saturation < 80%); severe hypotension (systolic blood pressure < 65 mm Hg or new or increased vasopressor administration); cardiac arrest; or death. Enrollment began on March 16, 2022 and is expected to be completed in 2023. Ethics and Dissemination: The trial protocol was approved with waiver of informed consent by the single institutional review board at Vanderbilt University Medical Center and the Human Research Protection Office of the Department of Defense. The results will be presented at scientific conferences and submitted for publication in a peer-reviewed journal. Trial Registration ClinicalTrials.gov registration (NCT05239195) on February 14, 2022, prior to the enrollment of the first patient.

IntroductionAmong critically ill patients undergoing orotracheal intubation in the emergency department (ED) or intensive care unit (ICU), failure to visualise the vocal cords and intubate the trachea on the first attempt is associated with an increased risk of complications. Two types of laryngoscopes are commonly available: direct laryngoscopes and video laryngoscopes. For critically ill adults undergoing emergency tracheal intubation, it remains uncertain whether the use of a video laryngoscope increases the incidence of successful intubation on the first attempt compared with the use of a direct laryngoscope.Methods and analysisTheDirEct versusVIdeo LaryngosCopE(DEVICE) trial is a prospective, multicentre, non-blinded, randomised trial being conducted in 7 EDs and 10 ICUs in the USA. The trial plans to enrol up to 2000 critically ill adults undergoing orotracheal intubation with a laryngoscope. Eligible patients are randomised 1:1 to the use of a video laryngoscope or a direct laryngoscope for the first intubation attempt. The primary outcome is successful intubation on the first attempt. The secondary outcome is the incidence of severe complications between induction and 2 min after intubation, defined as the occurrence of one or more of the following: severe hypoxaemia (lowest oxygen saturation <80%); severe hypotension (systolic blood pressure <65 mm Hg or new or increased vasopressor administration); cardiac arrest or death. Enrolment began on 19 March 2022 and is expected to be completed in 2023.Ethics and disseminationThe trial protocol was approved with waiver of informed consent by the single institutional review board at Vanderbilt University Medical Center and the Human Research Protection Office of the Department of Defense. The results will be presented at scientific conferences and submitted for publication in a peer-reviewed journal.Trial registration numberClinicalTrials.gov Registry (NCT05239195).