Minimal residual disease in Myeloma: Application for clinical care and new drug registration

The development of novel agents has transformed the treatment paradigm for multiple myeloma, with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow–based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in patients with multiple myeloma. Complementary liquid biopsy–based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid–based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real-world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory multiple myeloma, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in multiple myeloma is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes

A structured telephone-delivered intervention to reduce problem alcohol use (Ready2Change): study protocol for a parallel group randomised controlled trial

Background: Current population surveys suggest around 20% of Australians meet diagnostic criteria for an alcohol use disorder. However, only a minority seek professional help due to individual and structural barriers, such as low health literacy, stigma, geography, service operating hours and wait lists. Telephone-delivered interventions are readily accessible and ideally placed to overcome these barriers. We will conduct a randomised controlled trial (RCT) to examine the efficacy of a standalone, structured telephone-delivered intervention to reduce alcohol consumption, problem severity and related psychological distress among individuals with problem alcohol use. Methods/design: This is a single site, parallel group, two-arm superiority RCT. We will recruit 344 participants from across Australia with problem alcohol use. After completing a baseline assessment, participants will be randomly allocated to receive either the Ready2Change (R2C) intervention (n = 172, four to six sessions of structured telephone-delivered intervention, R2C self-help resource, guidelines for alcohol consumption and stress management pamphlets) or the control condition (n = 172, four phone check-ins < 5 min, guidelines for alcohol consumption and stress management pamphlets). Telephone follow-up assessments will occur at 4-6 weeks, 3 months, 6 months and 12 months post-baseline. The primary outcome is the Alcohol Use Disorders Identification Test (AUDIT) score administered at 3 months post-baseline. Secondary outcomes include change in AUDIT score (6 and 12 months post-baseline), change in number of past-month heavy drinking days, psychological distress, health and wellbeing, quality of life, client treatment evaluation and cost effectiveness. Discussion: This study will be one of the first RCTs conducted internationally to examine the impact of a standalone, structured telephone-delivered intervention to address problem alcohol use and associated psychological morbidity. The proposed intervention is expected to contribute to the health and wellbeing of individuals who are otherwise unlikely to seek treatment through mainstream service models, to reduce the burden on specialist services and primary care providers and to provide an accessible and proportionate response, with resulting cost savings for the health system and broader community. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12618000828224. Pre-registered on 16 May 2018

Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts. METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts. RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts. CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies

Models of classroom assessment for course-based research experiences

Course-based research pedagogy involves positioning students as contributors to authentic research projects as part of an engaging educational experience that promotes their learning and persistence in science. To develop a model for assessing and grading students engaged in this type of learning experience, the assessment aims and practices of a community of experienced course-based research instructors were collected and analyzed. This approach defines four aims of course-based research assessment—(1) Assessing Laboratory Work and Scientific Thinking; (2) Evaluating Mastery of Concepts, Quantitative Thinking and Skills; (3) Appraising Forms of Scientific Communication; and (4) Metacognition of Learning—along with a set of practices for each aim. These aims and practices of assessment were then integrated with previously developed models of course-based research instruction to reveal an assessment program in which instructors provide extensive feedback to support productive student engagement in research while grading those aspects of research that are necessary for the student to succeed. Assessment conducted in this way delicately balances the need to facilitate students’ ongoing research with the requirement of a final grade without undercutting the important aims of a CRE education

The formation of interpersonal and learning relationships in the transition from primary to secondary school: students, teachers and school context

The importance of relationships in education has been well established in the literature. However, the nature of relationship is seldom defined and as a result interpersonal and learning relationships are conflated and so implicitly treated as synonymous. In this paper we argue that learning relationships are different from interpersonal relationships, but crucially that interpersonal relationships are a pre-requisite to learning relationships. We define learning relationships as those which allow for the emergence of, and passage through, the zone of proximal development. At present there is a paucity of research which examines relationship formation of any type in education and in this paper we seek to address this gap. At the point of transition from one school to another there is a normative imperative to form new relationships. This paper focuses on the experiences of students in their transition to secondary school and explores the formation of relationships with their new teachers. An ethnographic method was employed which followed children during their final year of primary school and into their first year of secondary school. Through student and staff voices and observational data, the opening and closing of opportunities for the formation of interpersonal relationships, and by extension, learning relationships, are explored. The paper presents data from three schools in the UK and identifies the themes of courtesy, rules and resistance, and school systems and pedagogical practice as key determinants in relationship formation. We acknowledge that these findings represent the focal schools, but argue that the data demonstrate that attention must be paid to the construction of enabling transition contexts to facilitate the formation of interpersonal relationships which may lead to learning relationships in the new school. We further call for more focussed research which explores the nature of learning relationships

Reference genome of California walnut, Juglans californica, and resemblance with other genomes in the order Fagales

Juglans californica, California walnut, is a vulnerable small tree that is locally abundant but restricted to woodland and chaparral habitats of Southern California threatened by urbanization and land use change. This species is the dominant species in a unique woodland ecosystem in California. It is one of 2 endemic California walnut species (family Juglandaceae). The other species, Northern California black walnut (J. hindsii), has been suggested controversially to be a variety of J. californica. Here, we report a new, chromosome-level assembly of J. californica as part of the California Conservation Genomics Project (CCGP). Consistent with the CCGP common methodology across ~150 genomes, we used Pacific Biosciences HiFi long reads and Omni-C chromatin-proximity sequencing technology to produce a de novo assembled genome. The assembly comprises 137 scaffolds spanning 551,065,703 bp, has a contig N50 of 30 Mb, a scaffold N50 of 37 Mb, and BUSCO complete score of 98.9%. Additionally, the mitochondrial genome has 701,569 bp. In addition, we compare this genome with other existing high-quality Juglans and Quercus genomes, which are in the same order (Fagales) and show relatively high synteny within the Juglans genomes. Future work will utilize the J. californica genome to determine its relationship with the Northern California walnut and assess the extent to which these 2 endemic trees might be at risk from fragmentation and/or climate warming

Transition to postgraduate study: postgraduate ecological systems and identity

This paper explores and examines the distal and proximal systems which construct social science postgraduate study in the UK and analyses the emergent identities of postgraduate students as they negotiate the multiple and interacting practices in their transition to study. The data represent part of a one-year research project, funded by the Higher Education Academy, in which staff and students from five UK universities participated. The paper takes a socio-cultural perspective and situates staff and students in the wider macro context of policy and practice surrounding postgraduate study as well as exploring the micro processes which construct the proximal experience of the transition. We argue that the silence surrounding postgraduate transition in the literature must be addressed in light of existing literature and the present research, both of which suggest that the systems which construct postgraduate study are complex and challenging to students, who do not always receive the support they require. We discuss the practices which implicitly assume expertise in postgraduate students in contrast to student self-identification as confused and struggling. Commonalities with other educational transitions are identified but we argue that there are distinct aspects to postgraduate transition which require greater breadth of research with both successful and unsuccessful postgraduate students