Emergence of SARS-CoV-2 subgenomic RNAs that enhance viral fitness and immune evasion.

Coronaviruses express their structural and accessory genes via a set of subgenomic RNAs, whose synthesis is directed by transcription regulatory sequences (TRSs) in the 5' genomic leader and upstream of each body open reading frame. In SARS-CoV-2, the TRS has the consensus AAACGAAC; upon searching for emergence of this motif in the global SARS-CoV-2 sequences, we find that it evolves frequently, especially in the 3' end of the genome. We show well-supported examples upstream of the Spike gene-within the nsp16 coding region of ORF1b-which is expressed during human infection, and upstream of the canonical Envelope gene TRS, both of which have evolved convergently in multiple lineages.

Persistent Eosinophilic Inflammation Is Not a Feature of Type 2 CRS Patients Failing Anti-IL-5R Therapy and Requiring Class Switching to Anti-IL-4/13.

Background: Type 2 inflammation dominates eosinophilic chronic rhinosinusitis (eCRS) and adult onset asthma. IL-4, -5, and -13 are prominent disease mediators. Disease control can be achieved with biologic therapies.

A phase I study of MLN4924 and belinostat in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.

Purpose: Relapsed and/or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome continue to have a poor prognosis with limited treatment options despite advancements in rational combination and targeted therapies. Belinostat (an HDAC inhibitor) and Pevonedistat (a NEDD8 inhibitor) have each been independently studied in hematologic malignancies and have tolerable safety profiles with limited single-agent activity. Preclinical studies in AML cell lines and primary AML cells show the combination to be highly synergistic, particularly in high-risk phenotypes such as p53 mutant and FLT-3-ITD positive cells.

Use of a Non-Endoscopic Capsule-Sponge Triage Test for Reflux Symptoms: Results From the NHS England Prospective Real-World Evaluation.

Background: Acid reflux is a common presentation in primary care leading to a high volume of referrals to endoscopy that are often normal.

Aims: To determine whether a non-endoscopic capsule sponge biomarker test could triage patients with low-risk reflux symptoms, reduce endoscopy waiting lists and identify Barrett's oesophagus in a real-world setting.

Methods: Patients with reflux symptoms on NHS endoscopy waiting lists who were offered a capsule sponge (test group) between February 2021 and August 2022 were included in this national multicentre prospective cohort study and compared with eligible patients on the standard endoscopy pathway (counterfactual group).

Using Functional Magnetic Resonance Imaging to Detect Differences in Micturition-Related Brain Activity Between Volitional and Involuntary Detrusor Contractions.

Introduction: Detrusor contractions can be classified as either volitional or involuntary. The latter are a hallmark of urge urinary incontinence. Understanding differences in neuroactivation associated with both types of contractions can help elucidate pathophysiology and therapeutic targets.