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Supplementary Data Table S1: general characterisctic of the different cohorts of patients Supplementary Data Table S2: characterisctic of Population A Supplementary Data Table S3: characterisctic of Population B Supplementary Data Table S4: characterisctic of Population C Supplementary Data Table S5: characterisctic of Population D Supplementary Data Table S6: Primer sequences Supplementary Data Table S7: Differentially expressed transcripts between IgLV3-21 + and - patients Supplementary Data Table S8: differentially expressed genes between IgLV3-21 + and - patients Supplementary Data Table S9: differentially expressed genes between IgLV3-21 + and - patients. Restricted to absolute fold-change > 1.5 and protein coding genes only Supplementary Data Table S10 Gene set Enrichment analysis between IgLV3-21 positive and negative patients

Purpose: Unmutated (UM) immunoglobulin heavy chain variable region (IgHV) status or IgHV3-21 gene usage is associated with poor prognosis in chronic lymphocytic leukemia (CLL) patients. Interestingly, IgHV3-21 is often co-expressed with light chain IgLV3-21, which is potentially able to trigger cell-autonomous BCR-mediated signaling. However, this light chain has never been characterized independently of the heavy chain IgHV3-21.Experimental Design: We performed total RNA sequencing in 32 patients and investigated IgLV3-21 prognostic impact in terms of treatment-free survival (TFS) and overall survival (OS) in 3 other independent cohorts for a total of 813 patients. IgLV3-21 presence was tested by real-time PCR and confirmed by Sanger sequencing.Results: Using total RNA sequencing to characterize 32 patients with high-risk CLL, we found a high frequency (28%) of IgLV3-21 rearrangements. Gene set enrichment analysis revealed that these patients express higher levels of genes responsible for ribosome biogenesis and translation initiation (P < 0.0001) as well as MYC target genes (P = 0.0003). Patients with IgLV3-21 rearrangements displayed a significantly shorter TFS and OS (P < 0.05), particularly those with IgHV mutation. In each of the three independent validation cohorts, we showed that IgLV3-21 rearrangements—similar to UM IgHV status—conferred poor prognosis compared with mutated IgHV (P < 0.0001). Importantly, we confirmed by multivariate analysis that this was independent of IgHV mutational status or subset #2 stereotyped receptor (P < 0.0001).Conclusions: We have demonstrated for the first time that a light chain can affect CLL prognosis and that IgLV3-21 light chain usage defines a new subgroup of CLL patients with poor prognosis. Clin Cancer Res; 24(20); 5048–57. ©2018 AACR.

Supplementary Data Figure S1. Determination of IgLV3-21 positivity by real-time PCR. Supplementary Data Figure S2: CLL-OS analysis including only CLL-related deaths. Supplementary Data Figure S3. Validation of the poor prognosis associated with IgLV3-21 usage in population C. Supplementary Data Figure S4. Validation of the poor prognosis of IgLV3-21 usage in population D. Supplementary Data Figure S5: prognostic impact of IgLV3-21 usage in the different CLL-IPI subgroups. Supplementary Data Figure S6. Immunogenetic features of IgLV3-21 patients. Supplementary Data Figure S7. CXCR4 surface expression is downregulated in IgLV3-21 patients.

Background: Knowledge Translation (KT) Frameworks are commonly used in healthcare settings to integrate evidence into practice. However, little is known about how these KT frameworks affect organisational change including culture and patient safety outcomes in healthcare settings. Methods: A systematic review was undertaken. Five databases: PubMed, CINAHL, Scopus, ProQuest and Web of Science were searched with publications screened from January 2016 – July 2021. A blinded screening process was undertaken by all authors and conflicts resolved through open discussion. The Mixed Methods Appraisal Tool (MMAT) was used for quality appraisal. Results: Database search yielded a total of 1498 results, with only four studies included for data extraction and narrative synthesis. Three studies reported on patient safety outcomes, using Translational Simulation, Comprehensive Unit-based Safety Program (CUSP)/ Translating Research Into Practice (TRIP) model and the Consolidated Framework for Implementation Research (CFIR) framework. Only one study reported on organisational culture and used the Best-Practice Spotlight Organization (BPSO) Program. Factors that inhibited successful KT framework implementation relate to organisational and workforce issues such as staff attrition and secondments, staff not being released for education and an absence of commitment to the program at the executive level. Establishing and maintaining effective lines of communication and transparent reporting resulted in successful implementation outcomes. Conclusion: Various KT frameworks and strategies are used across healthcare settings to guide the development and evaluation of implementation projects and quality improvement initiatives. However, the impact of knowledge translation strategies on organisational culture and patient outcomes remains unclear, poorly described and under researched. Future research needs to be undertaken to explore the barriers and facilitators of knowledge translation processes and its impact on organisational change, culture and patient safety outcomes. Protocol Registration: This review was registered with the international prospective register of systematic reviews (PROSPERO), ID: CRD42021265470on 02/07/21. The design and methods used for this systematic review will be informed by and comply with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Moher et al., 2015).

Intrusion of sediment-derived hydrogen sulfide into above-ground tissues of seagrasses is correlated with reduced growth and has been linked to large-scale die-offs of Thalassia testudinum in Florida Bay, USA. In May of 2019, leaves from T. testudinum short shoots at 350 sites within 13 basins across Florida Bay were collected to investigate bay-wide variation in a novel, stable sulfur isotope-based indicator of hydrogen sulfide intrusion [(δ34Sleaf + 30)/total sulfur content]. The components of this sediment stress indicator (SSI), total sulfur content (% dry weight) and δ34S, were negatively correlated (R2 = -0.24), indicating greater sediment sulfide exposure in plants with higher sulfur content. Generalized additive model selection revealed that SSI was best predicted by a model which included T. testudinum cover, sediment depth, and Halodule wrightii cover (R2 = 0.24, weight = 0.48). Macrophyte communities dominated by dense T. testudinum climax communities and with deep sediments, which are characteristics associated with die-off, had the lowest SSI values, indicating greatest sulfide intrusion. Sites within the area of a recent (2015) seagrass die-off had significantly higher SSI values than nearby, non-die-off-affected sites (mean ± SE: 44.1 ± 1.5 vs. 40.2 ± 1.6, Wilcoxon p < 0.05). The recent die-off sites also had lower T. testudinum cover and higher H. wrightii cover than the non-die-off sites, indicating they were in the midst of recovery and at an early successional stage. Our findings indicate that SSI may provide a minimally destructive indicator of chronic sulfide intrusion in T. testudinum in Florida Bay.

In the wake of the death of King Goodwill Zwelithini on 12 March 2021, three historians of KwaZulu-Natal came together to discuss the historiography on the Zulu monarchs. Jabulani Sithole (JS), Liz...

Digital learning objects are new kinds of resources which teacher librarians will be required to manage and make accessible to teachers and students. In Australia there are currently large-scale national and state initiatives underway to develop a critical mass of learning objects. The development of a Learning System Architecture has also become a vital step to make it possible to manage these learning objects. Packages that will enable students and teachers to communicate, collaborate, locate and access resources within intellectual property arrangements, assemble digital resources into learning sequences, assess and report are all necessary requirements. The Learning System Architecture emerging in Australia enables these disparate systems to function together as seamless and interoperable packages. A new profile of teacher librarian competency is being developed in Tasmania to assist with planning the professional learning needs of this group. The new profile includes understandings and experience of information communication technologies and online learning. Managing these new digital resources to support the teaching and learning is a key new professional role for teacher librarians.

Hb J-Paris-I [HBA2: c.38C>A (or HBA1)] is a stable fast-moving hemoglobin (Hb) that elutes in the P3 window on high performance liquid chromatography (HPLC). The mutation can happen on either the α1- or α2-globin gene. Codon 12 changes from GCC to GAC to replace the alanine amino acid with aspartic acid. This change is external with no clinical significance. The elution in the P3 wave on HPLC can interfere with the glycated Hb assay by HPLC. In this study, data of 11 cases of Hb J-Paris-I were thoroughly presented. The majority of the cases were of Indian ethnicity. The mean value of Hb J-Paris-I on HPLC was 26.7 ± 2.0%. The retention time (RT) was 1.75 ± 0.03 min. The isoelectric focusing (IEF) mean value was -5.6 (range -6.1 to -4.9). Hb A2 was consistently reduced to 1.8 ± 0.3%. A fraction of 0.8% corresponding to the Hb A2-J-Paris-I (α2J-Paris-Iδ2) is likely to be concealed within the A0 peak of Hb A on HPLC. Interestingly, two cases were associated with two different polymorphisms [HBA2: c.-24C>G or Cap +14 (C>G) and HBA2: c.*136A>G polymorphism] without apparent effect on the variant expression.

Background Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2. Methods We provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day. Results Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation. Conclusions In this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy. (Funded by Gilead Sciences.)

Hb Winnipeg [α75(EF4)Asp→Tyr (α2); HBA2: c.226G>T (or HBA1)] is a stable α-globin chain variant described in a few articles. The majority of reported cases in older articles were clustered in Canada. It can occur on both α1- and α2-globin genes and in different populations. In this study, eight cases of Hb Winnipeg were characterized by DNA sequencing during a wide-spectrum study of suspected α-globin gene variants collected in the United Kingdom. All cases detected peaked in the S window between 4.4 and 4.54 min. on high performance liquid chromatography (HPLC). The isoelectric focusing (IEF) averaged at 6.21 below Hb A. All the mutations were detected on the α1-globin gene except in one case. The ethnic origin of the majority of the patients was Canadian. Only one case was associated with the common polymorphism HBA2: c.-24C>G (or HBA1) [Cap +14 (C>G)] on both α-globin genes without any apparent effect on the variant expression. All cases were detected in a heterozygous state. Hb Winnipeg expression was consistently lower than the theoretical value for α chain variants, ranging between 11.8 and 15.8% of total hemoglobin (Hb). This study gave more details about Hb Winnipeg that may help in presumptive diagnosis, especially in routine laboratories.

Hb J-Meerut [HBA2: c.362C>A (or HBA1)] is a rare, stable, nonpathogenic α-globin gene variant that peaks in the area between the P3 and A0 windows on high performance liquid chromatography (HPLC). ...

Over many years, cases of suspected α-globin chain variants were collected from different parts of the UK. The suspicion was based on the clinical picture, high performance liquid chromatography (HPLC) variant percentage, retention time (RT) and isoelectric focusing (IEF). DNA sequencing and the restriction enzyme E

This research project seeks to investigate the academic writing development of three students in the foundational first year unit ‘Academic Communication in Business and Economics’ (ACBE100) at Macquarie University. This unit aims to support students in their transition to university by enabling them to understand and achieve the necessary standards of performance required to be successful in an academic environment. This study was designed to be an intervention within the Macquarie Longitudinal Learner Corpus (MQLLC) research project currently being conducted by Dr Cassandra Liardet and her research team at Macquarie University. Participants are student volunteers studying the ACBE100 unit and were recruited from the larger MQLLC project. Writing development is explored from the students’ perspective through repeated use of a formative self-assessment tool, which aims to measure the accuracy with which the students are able to evaluate themselves in comparison to a researcher’s linguistic analysis of their written texts. Additionally, interviews regarding perspectives on the self assessment process were conducted with the students and a tutor. A linguistic perspective on the students’ writing development is provided through textual analysis encompassing genre, periodic structure and thematic development. These perspectives seek to illuminate the relationship between explicit teaching of linguistic features of academic writing and students’ writing development. This study employs a Systemic Functional Linguistics theoretical framework (see Halliday, 1993; Martin & Rose, 2008; Schleppegrell, 2001,2004) for mapping and examining language features.

Hb J-Paris-I [

Purpose: Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice. Methods: We used as a truthset 7541 dichotomous functional classifications of BRCA1 and MSH2, spanning 311 codons of BRCA1 and 918 codons of MSH2, generated from large-scale functional assays that have been shown to correlate excellently with clinical classifications. We assessed PM5 at 5 stringencies with incorporation of 8 in silico tools. For each analysis, we quantified a positive likelihood ratio (pLR, true positive rate/false positive rate), the predictive value of PM5-lookup in ClinVar compared with the functional truthset. Results: pLR was 16.3 (10.6-24.9) for variants for which there was exactly 1 additional colocated deleterious variant on ClinVar, and the variant under examination was equally or more damaging when analyzed using BLOSUM62. pLR was 71.5 (37.8-135.3) for variants for which there were 2 or more colocated deleterious ClinVar variants, and the variant under examination was equally or more damaging than at least 1 colocated variant when analyzed using BLOSUM62. Conclusion: These analyses support the graded use of PM5, with potential to use it at higher evidence weighting where more stringent criteria are met.

Hb Winnipeg [α75(EF4)Asp→Tyr (α2)