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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]

Background: Despite achievements in the reduction of malaria globally, imported malaria cases to the United States by returning international travelers continue to increase. Immigrants to the United States from sub-Saharan Africa (SSA) who then travel back to their homelands to visit friends and relatives (VFRs) experience a disproportionate burden of malaria illness. Various studies have explored barriers to malaria prevention among VFRs and non-VFRs–travelers to the same destinations with other purpose for travel–but few employed robust epidemiologic study designs or performed comparative analyses of these two groups. To better quantify the key barriers that VFRs face to implement effective malaria prevention measures, we conducted a comprehensive community-based, cross-sectional, survey to identify differences in malaria prevention knowledge, attitudes, and practices (KAP) among VFRs and others traveling to Africa and describe the differences between VFRs and other types of international travelers. Methods and findings: Three distinct populations of travelers with past or planned travel to malaria-endemic countries of SSA were surveyed: VFRs diagnosed with malaria as reported through a state health department; members of the general VFR population (community); and VFR and non-VFR travelers presenting to a travel health clinic, both before their pretravel consultation and again, after return from travel. A Community Advisory Board of African immigrants and prior qualitative research informed survey development and dissemination. Across the three groups, 489 travelers completed surveys: 351 VFRs and 138 non-VFRs. VFRs who reported taking antimalarials on their last trip rated their concern about malaria higher than those who did not. Having taken five or more trips to SSA was reported more commonly among VFRs diagnosed with malaria than community VFRs (44.0% versus 20.4%; p = 0.008). Among travel health clinic patients surveyed before and after travel, VFR travelers were less successful than non-VFRs in adhering to their planned use of antimalarials (82.2% versus 98.7%; p = 0.001) and employing mosquito bite avoidance techniques (e.g., using bed nets: 56.8% versus 81.8%; p = 0.009). VFRs who visited the travel health clinic were more likely than VFR respondents from the community to report taking an antimalarial (83.0% versus 61.9%; p = 0.009), or to report bite avoidance behaviors (e.g., staying indoors when mosquitoes were out: 80.9% versus 59.5%; p = 0.009). Conclusions: We observed heterogeneity in malaria prevention behaviors among VFRs and between VFR and non-VFR traveler populations. Although VFRs attending the travel health clinic appear to demonstrate better adherence to malaria prevention measures than VFR counterparts surveyed in the community, specialized pretravel care is not sufficient to ensure chemoprophylaxis use and bite avoidance behaviors among VFRs. Even when seeking specialized pretravel care, VFRs experience greater barriers to the use of malaria prevention than non-VFRs. Addressing access to health care and upstream barrier reduction strategies that make intended prevention more achievable, affordable, easier, and resonant among VFRs may improve malaria prevention intervention effectiveness. [ABSTRACT FROM AUTHOR]

Background: Plasma cell dyscrasias (PCD) are a spectrum of disorders resulting from the clonal expansion of plasma cells, ranging from the pre-malignant condition monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM). MM generates a significant burden of disease on the community and it is predicted that it will increase in both incidence and prevalence owing to an ageing population and longer survival secondary to new therapeutic options. Robust and comprehensive clinical data are currently lacking but are required to define current diagnostic, investigational and management patterns in Australia and New Zealand (ANZ) for comparison to both local and international guidelines for standards of care. A clinical registry can provide this information and subsequently support development of strategies to address any differences, including providing a platform for clinical trials. The Myeloma and Related Diseases Registry (MRDR) was developed to monitor and explore variations in practices, processes and outcomes in ANZ and provide benchmark outcomes nationally and internationally for PCD. This paper describes the MRDR aims, development and implementation and discusses challenges encountered in the process. Methods: The MRDR was established in 2012 as an online database for a multi-centre collaboration across ANZ, collecting prospective data on patients with a diagnosis of MGUS, MM, solitary plasmacytoma or plasma cell leukaemia. Development of the MRDR required multi-disciplinary team participation, IT and biostatistical support as well as financial resources. Results: More than 1250 patients have been enrolled at 23 sites to date. Here we describe how database development, data entry and securing ethics approval have been major challenges for participating sites and the coordinating centre, and our approaches to resolving them. Now established, the MRDR will provide clinically relevant and credible monitoring, therapy and 'real world' outcome data, to support the conduction of high quality studies. In addition, the Myeloma 1000 sub-study is establishing a repository of paired peripheral blood specimens from registry patients to study mechanisms underlying disease progression. Conclusion: Establishment of the MRDR has been challenging, but it is a valuable investment that will provide a platform for coordinated national and international collaboration for clinical research in PCD in ANZ. [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]