Scaffold-enabled high-resolution cryo-EM structure determination of RNA.

Cryo-EM structure determination of protein-free RNAs has remained difficult with most attempts yielding low to moderate resolution and lacking nucleotide-level detail. These difficulties are compounded for small RNAs as cryo-EM is inherently more difficult for lower molecular weight macromolecules. Here we present a strategy for fusing small RNAs to a group II intron that yields high resolution structures of the appended RNA.

Safety and Efficacy of Deutetrabenazine at High versus Lower Daily Dosages in the ARC-HD Study to Treat Chorea in Huntington Disease.

Background: Huntington disease (HD) is a progressive neurodegenerative disease that causes psychiatric and neurological symptoms, including involuntary and irregular muscle movements (chorea). Chorea can disrupt activities of daily living, pose safety issues, and may lead to social withdrawal. The vesicular monoamine transporter 2 inhibitors tetrabenazine, deutetrabenazine, and valbenazine are approved treatments that can reduce chorea.

Performance of the High-STEACS Early Rule Out Pathway Using hs-cTnT at 30 Days in a Multisite US Cohort.

Background: The High-STEACS (High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome) pathway risk stratifies emergency department patients with possible acute coronary syndrome. This study aims to determine if the High-STEACS hs-cTnT (high-sensitivity cardiac troponin T) pathway can achieve the ≥99% negative predictive value (NPV) safety threshold for 30-day cardiac death or myocardial infarction (CDMI) in a multisite US cohort of patients with and without known coronary artery disease (CAD).

Methods: A secondary analysis of the STOP-CP (High-Sensitivity Cardiac Troponin T [Gen 5 STAT Assay] to Optimize Chest Pain Risk Stratification) cohort, which enrolled adult emergency department patients with possible acute coronary syndrome at 8 US sites (January 25, 2017-September 6, 2018).

Covered Stent Correction for Sinus Venosus Atrial Septal Defects, an Emerging Alternative to Surgical Repair: Results of an International Registry.

Background: Covered stent correction for a sinus venosus atrial septal defect (SVASD) was first performed in 2009. This innovative approach was initially viewed as experimental and was reserved for highly selected patients with unusual anatomic variants. In 2016, increasing numbers of procedures began to be performed, and in several centers, it is now offered as a standard of care option alongside surgical repair.

Structural variant allelic heterogeneity in MECP2 duplication syndrome provides insight into clinical severity and variability of disease expression.

Background: MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXSL families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ copy number variant breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated.

Relationship Between Severity of Ischemia and Coronary Artery Disease for Different Stress Test Modalities in the ISCHEMIA Trial.

Background: The relationship between the extent and severity of stress-induced ischemia and the extent and severity of anatomic coronary artery disease (CAD) in patients with obstructive CAD is multifactorial and includes the intensity of stress achieved, type of testing used, presence and extent of prior infarction, collateral blood flow, plaque characteristics, microvascular disease, coronary vasomotor tone, and genetic factors. Among chronic coronary disease participants with site-determined moderate or severe ischemia, we investigated associations between ischemia severity on stress testing and the extent of CAD on coronary computed tomography angiography.

Methods: Clinically indicated stress testing included nuclear imaging, echocardiography, cardiac magnetic resonance imaging, or nonimaging exercise tolerance test.

Comprehensive landscape analysis for usable real-world wound care data.

Background: The Wound Care Collaborative Community (WCCC) aims to assess current usable real-world data (RWD) sources to determine which real-world databases (DBs) are suitable and usable for studying the natural history of chronic wounds. Randomized controlled trials (RCTs) do not fully reflect the complexity of patients with chronic wounds. Using RWD, establishment of a scientifically grounded "road map" for RCTs is needed to better navigate the real-world complexity of the patients with chronic wounds.

Pregnancy outcomes with the pregestational use of Minimed 780G compared to Minimed 640G: findings from a multicenter cohort study.

Aim: To compare glycemic control and maternal-fetal outcomes of women with type 1 diabetes (T1D) using Minimed™ 780G (MM780G) with those women using Minimed™ 640G (MM640G) since before pregnancy.

Methods: Multicenter prospective cohort study of pregnant women with T1D in Spain. We evaluated HbA1c, time spent within (TIRp), below (TBRp) and above (TARp) the pregnancy-specific glucose range 3.

Integrating Out-of-Pocket Costs Into Shared Decision-Making for Heart Failure With Reduced Ejection Fraction: A Stepped-Wedge Trial (POCKET-COST-HF).

Background: Guideline-directed medical therapy for heart failure (HF) with reduced ejection fraction can entail high out-of-pocket (OOP) costs, prompting concerns about financial toxicity and access. OOP costs are generally unavailable during encounters. This trial assessed the impact of providing patient-specific OOP costs to patients and clinicians.

The thermodynamic principles of isochoric freezing pressure-aided supercooling.

This study outlines a method for designing an isochoric (constant volume) system to reduce the supercooling preservation temperature without affecting the likelihood of ice nucleation and without the need for cryoprotective additives. The method involves a multiphase system wherein the biological material is separated from a second aqueous solution by a boundary that transfers pressure and heat but not mass. The pressure within the system is passively increased by the confined growth of ice within the secondary solution.

Receptor-dependent influence of R7 RGS proteins on neuronal GIRK channel signaling dynamics.

Most neurons are influenced by multiple neuromodulatory inputs that converge on common effectors. Mechanisms that route these signals are key to selective neuromodulation but are poorly understood. G protein-gated inwardly rectifying K (GIRK or Kir3) channels mediate postsynaptic inhibition evoked by G protein-coupled receptors (GPCRs) that signal via inhibitory G proteins.

Efficacy of Radicava® IV (intravenous edaravone) in subjects with differing trajectories of disease progression in amyotrophic lateral sclerosis: Use of a novel statistical approach for post hoc analysis of a pivotal phase 3 clinical trial.

Introduction: Subjects with amyotrophic lateral sclerosis (ALS) treated with Radicava® (edaravone) IV (intravenous; Mitsubishi Tanabe Pharma America [MTPA], hereafter "MTPA IV edaravone") in Study MCI186-19 had a significantly slower physical functional decline vs placebo-treated subjects as measured by the revised ALS Functional Rating Scale (ALSFRS-R) and analyzed by the linear mixed model for repeated measures (MMRM). This Study 19 post hoc analysis of MTPA IV edaravone-treated and placebo-treated subjects evaluated linear and nonlinear latent class mixed models defining trajectories based on identifying the model with the lowest Bayesian information criterion. The best model differentiated 4 nonlinear trajectories in ALS subjects.

Integrated multi-omics analysis of zinc-finger proteins uncovers roles in RNA regulation.

RNA interactome studies have revealed that hundreds of zinc-finger proteins (ZFPs) are candidate RNA-binding proteins (RBPs), yet their RNA substrates and functional significance remain largely uncharacterized. Here, we present a systematic multi-omics analysis of the DNA- and RNA-binding targets and regulatory roles of more than 100 ZFPs representing 37 zinc-finger families. We show that multiple ZFPs are previously unknown regulators of RNA splicing, alternative polyadenylation, stability, or translation.

Regulation of Hippocamposeptal Synaptic Transmission by GABARs Is Altered in 5XFAD Mice in a Sex- and Age-Dependent Manner.

Hippocamposeptal (HS) neurons send GABAergic projections from the hippocampus to the medial septum/diagonal band of Broca (MS/DBB) as part of a reciprocal loop that is critical for memory. HS neurons are proposed to be particularly sensitive to the deleterious effects of pathological exposure to amyloid-β (Aβ), as would occur during Alzheimer's disease (AD). However, it is not known how HS GABA release in the MS/DBB is altered during the progression of AD.