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Background Tapencarium (RZL-012) (5-(3.6-dibromo-9H-carbazol-9-yl)-N, N, N-trimethylpentan-1-aminium chloride) is a novel injectable synthetic molecule with cytolytic properties, capable of reducing subcutaneous fat volume. Objectives The goal of this 3-armed, randomized, double-blind, placebo-controlled phase 2b study was to determine the safety and efficacy of low- and high-dose RZL-012 vs placebo on submental fat (SMF) reduction. Methods Patients (n = 151, age 18-65 years) with excess SMF received a single treatment session of RZL-012 or placebo in the submental area, after which they were monitored for 84 days. SMF was assessed at baseline and after dosing with newly developed scales, namely the Clinician Chin Assessment Tool (C-CAT) and Subject Chin Assessment Tool (S-CAT). SMF was also assessed by magnetic resonance imaging (MRI) at screening and on Day 84 after treatment. Results The proportion of patients who had a 1-grade or 2-grade improvement in C-CAT and/or S-CAT on Day 84 vs baseline was significantly higher in the high-dose RZL-012 group vs the placebo group (P <.002). The relative percentage reduction in MRI-measured SMF volume (Day 84 vs screening) was significantly greater in the high-dose RZL-012 group vs the low-dose RZL-012 or the placebo group (P <.0001). Local injection site reactions were the most common adverse events (AEs). Conclusions A single administration of RZL-012 into SMF resulted in significant improvement in submental appearance as assessed by clinicians, patients, and MRI. From a safety perspective, there were no serious AEs and no clinically significant changes in vital signs or laboratory tests over the course of the study. Level of Evidence: 1 [ABSTRACT FROM AUTHOR]

To prevent or mitigate chronic illness burden, people with cystic fibrosis (pwCF) and their family caregivers need primary (generalist-level) palliative care from the time of diagnosis forward. We used qualitative methods to explore their preferences about a screening-and-triage model (" Improving Life with CF ") developed to standardize this care. We purposively sampled and interviewed 14 pwCF and caregivers from 5 Improving Life with CF study sites. Thematic analysis was guided by a priori codes using the National Consensus Project's Guidelines for Quality Palliative Care. Participants included 7 adults and 2 adolescents with CF (3 with advanced disease), 4 parents, 1 partner (7 women; 5 people of color). Few were familiar with palliative care. Illness burden was described in multiple domains, including physical (e.g., dyspnea, pain), psychological (e.g., anxiety), and social (e.g., family well-being; impact on work/school). Most preferred survey-based screening with care coordination by the CF team. Preferences for screening approaches varied. PwCF and caregivers experience illness burden and are receptive to a CF-team delivered primary palliative care screening-and-triage model with flexible processes. [ABSTRACT FROM AUTHOR]

Natural transformation is the process by which bacteria actively take up and integrate extracellular DNA into their genomes. In cyanobacteria, natural transformation has only been experimentally demonstrated in a few species. Although cyanobacteria are important model systems for studying photosynthesis and circadian cycling, natural transformation in cyanobacteria has not been characterized to the degree that the process has been studied in other Gram-negative bacteria. Two cyanobacterial species that are 99.8% genetically identical provide a unique opportunity to better understand the nuances of natural transformation in cyanobacteria: Synechococcus elongatus PCC 7942 and Synechococcus elongatus UTEX 2973 (hereafter called Synechococcus 7942 and Synechococcus 2973, respectively). Synechococcus 7942 is a naturally transformable model system, while Synechococcus 2973 is a recently discovered species that is not naturally competent. Taking only 1.5 h to replicate, Synechococcus 2973 is the fastest-growing cyanobacterial species known and thus is a strong candidate for serving as a model organism. However, its inability to undergo natural transformation has prevented it from becoming a widely used model system. By substituting polymorphic alleles from Synechococcus 7942 for native Synechococcus 2973 alleles, natural transformation was introduced into Synechococcus 2973. Two genetic loci were found to be involved in differential natural competence between the two organisms: transformation pilus component pilN and circadian transcriptional master regulator rpaA. By using targeted genome editing and enrichment outgrowth, a strain that was both naturally transformable and fast-growing was created. This new Synechococcus 2973-T strain will serve as a valuable resource to the cyanobacterial research community. [ABSTRACT FROM AUTHOR]

The Bruton tyrosine kinase (BTK) inhibitor, zanubrutinib, was designed for high BTK specificity and minimal toxicity. SEQUOIA (NCT03336333) is a global, open-label, randomized phase 3 study in treatment-naive patients with CLL//SLL without del(17p) who were unsuitable for fludarabine//cyclophosphamide/rituximab. Patients were randomized to receive zanubrutinib (160 mg twice daily) or bendamustine (day 1-2: 90 mg/m²) and rituximab (cycle 1: 375 mg/m²; cycles 2-6: 500 mg/m²); stratification factors were age (<65 y vs. ≥65 y), Binet Stage, IGHV mutation, and geographic region. Primary endpoint was independent review committee (IRC)-assessed progression-free survival (PFS). Secondary endpoints included investigator-assessed (INV) PFS, overall response rate (ORR), overall survival (OS), and safety. From 31 Oct 2017-22 Jul 2019, 479 patients were enrolled (zanubrutinib = 241; BR = 238). Baseline characteristics (zanubrutinib vs. BR): median age, 70.0 y vs. 70.0 y; unmutated IGHV, 53.4% vs. 52.4%; del(11q), 17.8% vs. 19.3%. With median follow-up of 26.2 mo, PFS was significantly prolonged with zanubrutinib by IRC (HR 0.42; 2-sided p <0.0001), and INV (HR 0.42; 2-sided p = = 0.0001). Zanubrutinib treatment benefit occurred across age, Binet stage, bulky disease, del(11q) status and unmutated IGHV (HR 0.24; 2-sided p <0.0001), but not mutated IGHV (HR 0.67; 2-sided p = 0.1858). For zanubrutinib vs. BR, 24-mo PFS-IRC = 85.5% vs. 69.5%; ORR-IRC = 94.6% vs. 85.3%; complete response rate = 6.6% vs. 15.1%; ORR-INV = 97.5% vs. 88.7%; and 24-mo OS = 94.3% vs. 94.6%. Select adverse event (AE) rates (zanubrutinib vs. BR): atrial fibrillation (3.3% vs. 2.6%), bleeding (45.0% vs. 11.0%), hypertension (14.2% vs. 10.6%), infection (62.1% vs. 55.9%), and neutropenia (15.8% vs. 56.8%). Treatment discontinuation due to AEs (zanubrutinib vs. BR) = = 20 patients (8.3%) vs. 31 patients (13.7%); AEs leading to death = 11 patients (4.6%) vs. 11 patients (4.8%). No sudden deaths occurred. In summary, zanubrutinib significantly improved PFS-IRC vs. BR and was well tolerated, supporting the potential utility of frontline zanubrutinib in treatment-naive CLL/SLL. [ABSTRACT FROM AUTHOR]

Amino sugars N-acetylglucosamine (GlcNAc) and glucosamine (GlcN) are abundant sources of carbon and nitrogen in the oral cavity. The aim of this study was to investigate the effects of GlcNAc metabolism on the genomics and biochemistry of a saliva-derived microbial community, and on the surface integrity of human teeth and restorative surfaces. Pooled cell-containing saliva (CCS) was used to establish a microcosm biofilm in vitro in a biofilm medium (BM) containing 5 different carbohydrates. The microbial composition of each biofilm was analyzed by 16S rRNA amplicon sequencing, and the concentrations of eight organic acids were determined for selected sugars by targeted metabolomics. Meanwhile, extracted human teeth and polished titanium and ceramic disks were submerged in BM supplemented with 1% of glucose or GlcNAc, inoculated with CCS and Streptococcus mutans UA159, and incubated for 30 days. To mimic the effects of other microbial byproducts, the specimens were immersed in 10 mM hydrogen peroxide and 10 mM ammonium hydroxide for 30 days. The surface of each specimen was evaluated by profilometry for roughness (Ra) and imaged by scanning electron microscopy. The pH of the biofilm supernatant was significantly higher for the medium containing GlcNAc (p < 0.0001), and was higher in samples containing teeth than the two restorative disks for media containing the same sugar. For both teeth and titanium specimens, the samples treated with glucose-biofilm presented higher roughness values (Ra) than those with GlcNAc-biofilm and every other group. SEM images of the teeth and titanium disks largely supported the profilometry results, with glucose-biofilm samples demonstrating the largest deviation from the reference. For ceramic disks, slightly higher Ra values were obtained for the ammonia group. These findings provide the first direct evidence to support the ability of amino sugars to significantly reduce the cariogenic potential of oral biofilms by altering their biochemistry and bacterial composition. Additionally, amino sugar metabolism appears to be less detrimental to teeth and restorative surfaces than glucose metabolism. [ABSTRACT FROM AUTHOR]