Despite ongoing attempts to disrupt the white cis-hetero-masculine nature of the literary canon the secondary school English curriculum remains tethered to its lineage. In conversation with feminist ...new materialist scholars who argue that the stories we read and write have material affects on who we are becoming, this paper argues that in order to mobilise change in the secondary years of schooling, interventions into the canon must move beyond (re)forming text lists or providing teachers with readymade pedagogical resources. Drawing on the Australian context, the authors outline some of the contemporary challenges teachers face in diversifying and decolonising the curriculum. Drawing on their Literary Linking Methodology the authors discuss a pilot project that seeks to unsettle the canon by supporting teachers to undertake extended immersion with both contemporary literary texts and archival research. Accordingly, this paper contributes to understandings of the tensions and challenges teachers face in introducing contemporary Australian texts into the curriculum and offers insights into the ways in which professional learning might be (re)imagined so that English teachers might draw on available cultural resources as researchers and literary knowledge producers in the twenty-first century.
Abstract Background and Aims Voclosporin is a second generation calcineurin inhibitor (CNI) approved for the treatment of adults with active lupus nephritis (LN) in combination with immunosuppressive ...therapy. An integrated analysis of the Phase 2 AURA-LV and Phase 3 AURORA 1 studies concluded that combining voclosporin with lower-dose mycophenolate mofetil (MMF, 2 g/day) and low-dose glucocorticoids (GCs) led to significantly greater and earlier reductions in proteinuria when compared to MMF and GCs alone. This is an important finding as early reduction in proteinuria is associated with improved long-term kidney survival and mortality. Yet, dual-immunosuppressive regimens consisting of high-dose glucocorticoids and either intravenous cyclophosphamide (IVC) or higher doses of MMF (>2 g/day) continue to be frequently used for the initial management of active LN despite their association with incomplete efficacy and dose-dependent toxicities. Method All three studies enrolled participants with active LN. In AURA-LV and AURORA 1, participants received voclosporin 23.7 mg BID in combination with MMF (target 2 g/day) and oral GCs (25 mg/day tapered to 2.5 mg/day by Week 16). In ALMS, MMF (target 3 g/day) or IVC (0.5 to 1.0 g/m2/month × 6) was added to oral GCs initiated at a maximum dose of 60 mg/day, tapered every 2 weeks to 10 mg/day. Propensity score methodology was used to generate groups of matched participants (ALMS MMF and IVC vs. AURA-LV/AURORA 1 voclosporin) based on demographic and disease characteristics. Safety and efficacy were assessed at 3 and 6 months. Results Propensity matching identified 179 pairs of participants with similar demographics and baseline disease characteristics. Mean cumulative exposure to GCs was more than 2-fold higher in the IVC and MMF cohorts of ALMS than AURA-LV/AURORA 1 participants over both 3 and 6 months. The overall incidence of adverse events (AEs) was higher in IVC- and MMF-treated participants of ALMS, although more participants in AURA-LV and AURORA 1 reported hypertension and anemia (Table 1). Due to the known hemodynamic effects of calcineurin inhibition, there was a small decrease in mean eGFR in the AURA-LV/AURORA 1 participants in the first few weeks of treatment after which mean eGFR remained stable; AURA-LV/AURORA 1 participants also had an increased rate of events of GFR decreased. The incidence of serious AEs was similar across treatments. In the first 3 months of treatment, significantly more AURA-LV/AURORA 1 participants achieved a reduction in UPCR >25% from baseline (91.6% vs 69.3%; odds ratio OR 4.75, 95% confidence interval CI 2.56, 8.84; p < 0.0001). Over six months of treatment, mean (SD) change from baseline in UPCR was −3.1 (2.9) g/g in voclosporin-treated patients in AURA-LV and AURORA 1 compared to −2.4 (3.3) g/g in IVC- or MMF-treated participants in ALMS (Fig. 1). Conclusion Voclosporin-based, triple immunosuppressive therapy was associated with an improved safety profile as well as greater and earlier reductions in proteinuria compared to more conventional dual immunosuppressive regimens. These data support treatment guidelines for active LN that recommend both minimizing patient exposure to GCs and use of a multi-targeted treatment regimen as initial therapy.
BackgroundGOSH is the largest Paediatric BMT centre in the UK, performing over 100 transplant procedures per year. Patient survival is increasing; complications associated with long term survival ...include functional difficulties and physical comorbidities. Evidence supports increasing activity and delivering physiotherapy through BMT to benefit functional and physical outcomes.Historically, the Physiotherapy service responding to problems in patients undergoing BMT was reactive. Referrals at crisis point were associated with loss of function and delayed discharge in some cases. With a small increase in staffing, a proactive service was developed aiming to keep children active through BMT whilst maintaining responsiveness to changing presentations.MethodTo ensure our service reflected evidence and clinical expertise, we systematically reviewed literature and experience across UK children’s hospitals. Consensus was sought regarding best practice within the GOSH MDT and an expert national group of Physiotherapists was established. A new Physiotherapy BMT service pathway was proposed.ResultsEvery family and patient listed for BMT is invited to attend a virtual pre-BMT multi-professionals clinic. Each patient completes age-appropriate baseline standardised assessments on admission and discharge. Regular, timetabled physiotherapy sessions, at least twice a week, are offered throughout admission. Increased physical activity on and off the ward is encouraged by the MDT. A physiotherapy information pack is provided on discharge and onward referrals to community services made where indicated. Anecdotally these referrals have reduced following the change in service. Physiotherapy is now also part of a complex GVHD MDT clinic.ConclusionPhysiotherapists are ideally positioned to pre-empt deterioration in function and reduce risk of secondary complications in patients going through BMT. The pro-active approach to the service changes have been well received by the MDT, families and patients. Long term follow-up by the MDT is indicated. A formal service evaluation of outcomes and experience is in process.
Dysfunction of interleukin-10 producing regulatory B cells has been associated with the pathogenesis of autoimmune diseases, but whether regulatory B cells can be therapeutically induced in humans is ...currently unknown. Here we demonstrate that a subset of activated B cells expresses CD25, and the addition of low-dose recombinant IL-2 to in vitro stimulated peripheral blood and splenic human B cells augments IL-10 secretion. Administration of low dose IL-2, aldesleukin, to patients increases IL-10-producing B cells. Single-cell RNA sequencing of circulating immune cells isolated from low dose IL2-treated patients reveals an increase in plasmablast and plasma cell populations that are enriched for a regulatory B cell gene signature. The transcriptional repressor BACH2 is significantly down-regulated in plasma cells from IL-2-treated patients, BACH2 binds to the IL-10 gene promoter, and Bach2 depletion or genetic deficiency increases B cell IL-10, implicating BACH2 suppression as an important mechanism by which IL-2 may promote an immunoregulatory phenotype in B cells.
BackgroundAn increase in the number of outpatient physiotherapy referrals for patients with Acute Lymphoblastic Leukaemia (ALL) was noticed between 2019 and 2021; a significant number of these were ...due to expected side-effects of steroid induction treatment.An audit was carried out in 2022 to look at the impact of early education provision in children following ALL diagnosis. The aim to see whether this reduced the impact of Induction chemotherapy side effects, and/or increase understanding for parents of expected side effects of treatment, thereby reducing the number of physiotherapy referrals and improving staffing resources. This concluded that there was a small reduction in the number of referrals. Positive feedback from Physiotherapists and families involved was received, however, timing of information delivery at diagnosis was suboptimal.An audit was repeated to determine whether providing education 2 weeks post-diagnosis was a more suitable time to families, thereby having a more significant impact to the number of physiotherapy referrals.MethodOur treatment group was all children with newly diagnosed ALL between Induction and Consolidation chemotherapy treatment blocks from April 2022 – July 2023. Education was provided to these group 2 weeks post-diagnosis and the number of physiotherapy referrals audited. Comparison was made to the number of referrals with no intervention group (January 2021 -September 2021) and with intervention at diagnosis group (September 2021-April 2022).Results61% of no intervention group were referred to physiotherapy, compared to 52% who were provided early education information at diagnosis, and 38% who were provided information 2 weeks post-diagnosis; this audit revealed a 23% reduction in referrals compared to the no intervention group. Positive feedback was received from families and Physiotherapists involved regarding content and timing of education delivery.ConclusionProviding early education 2 weeks post-diagnosis reduced the number of physiotherapy referrals between Induction and end of Consolidation.
ObjectiveEarly reduction in proteinuria after initial treatment has been associated with improved long-term kidney outcomes in lupus nephritis (LN). The addition of voclosporin, a second generation ...calcineurin inhibitor, to MMF and low-dose glucocorticoids (GC)s led to greater reductions in proteinuria compared to conventional therapy in the AURA-LV and AURORA 1 studies with an acceptable safety profile. Using propensity-matched participants from the voclosporin clinical trials and ALMS, we tested the hypothesis that a voclosporin-based, triple immunosuppressive regimen results in improved safety without compromising efficacy. MethodsIn AURA-LV and AURORA 1, voclosporin 23.7 mg BID was combined with MMF (2 g/day) and oral GCs (25 mg/day tapered to 2.5 mg/day by Week 16). In ALMS, MMF (3 g/day) or intravenous cyclophosphamide (IVC; 0.5 to 1.0 g/m2/month x 6) was added to oral GCs initiated at a maximum dose of 60 mg/day, tapered every 2 weeks to 10 mg/day. Propensity score methodology was used to generate groups of matched participants (ALMS vs. AURA-LV/AURORA 1) based on demographic and disease characteristics. Safety and efficacy were assessed at 3 and 6 months. ResultsA total of 179 matched pairs were identified. As expected, cumulative GC exposure was 2-fold higher in ALMS at 3 and 6 months. The incidence of adverse events (AEs) was higher in IVC- and high-dose MMF-treated participants (table 1), although more voclosporin-treated participants reported AEs of GFR decrease and hypertension; the incidence of serious AEs was similar with all treatments. At 6 months, the proportion of participants achieving >50% UPCR reduction from baseline was significantly greater in the voclosporin arm (p=0.005).ConclusionA voclosporin-based triple immunosuppressive regimen (voclosporin, MMF, and low-dose GCs) has a better overall safety profile than double-therapy regimens, with specific AEs attributable to higher-dose GCs, higher-dose MMF and IVC in the latter. Triple therapy is also superior in achieving early proteinuria milestones. These data provide further support for use of combination therapy as initial treatment in patients with active LN and to minimizing patient exposure to GCs, as proposed by the 2023 EULAR guidelines. AcknowledgementThis study was funded by Aurinia Pharmaceuticals Inc. Abstract P87 Table 1Select safety outcomes % (n) 3 Months 6 Months ALMS AURA-LV/AURORA 1 ALMS AURA-LV/AURORA1 IVC N=91 MMF N=88 Voclosporin N=179 IVC N=91 MMF N=88 Voclosporin N=179 Any AE 91.2 (83) 94.3 (83) 83.2 (149) 95.6 (87) 95.5 (84) 89.9 (161) Serious AE 12.1 (11) 22.7 (20) 14.5 (26) 15.4 (14) 25.0 (22) 19.6 (35) AEs by System Organ Class,% (n) Gastrointestinal disorders 59.3 (54) 52.3 (46) 34.6 (62) 65.9 (60) 61.4 (54) 38.5 (69) Infections and infestations 46.2 (42) 60.2 (53) 41.9 (75) 58.2 (53) 72.7 (64) 54.2 (97) Skin and subcutaneous tissue disorders 47.3 (43) 28.4 (25) 19.6 (35) 56.0 (51) 37.5 (33) 24.0 (43) Musculoskeletal/connective tissue disorders 34.1 (31) 29.5 (26) 19.6 (35) 44.0 (40) 37.5 (33) 24.6 (44) Blood and lymphatic system disorders 20.9 (19) 13.6 (12) 11.7 (21) 40.7 (37) 23.9 (21) 18.4 (33) Psychiatric disorders 13.2 (12) 17.0 (15) 2.2 (4) 15.4 (14) 17.0 (15) 3.4 (6) Endocrine disorders 11.0 (10) 8.0 (7) 1.1 (2) 11.0 (10) 8.0 (7) 1.1 (2) Reproductive system and breast disorders 9.9 (9) 6.8 (6) 2.2 (4) 12.1 (11) 8.0 (7) 2.2 (4) Renal and urinary disorders 6.6 (6) 4.5 (4) 7.3 (13) 8.8 (8) 9.1 (8) 10.6 (19) AEs by Preferred Term,% (n) GFR decreased 0 (0) 0 (0) 18.4 (33) 0 (0) 0 (0) 24.6 (44) Hypertension 8.8 (8) 10.2 (9) `15.6 (28) 12.1 (11) 14.8 (13) 17.3 (31) In AURA-LV and AURORA 1, voclosporin 23.7 mg BID was combined with MMF (2 g/day) and oral GCs (25 mg/day tapered to 2.5 mg/day by Week 16). In ALMS, MMF (3 g/day) or intravenous cyclophosphamide (IVC; 0.5 to 1.0 g/m2/month x 6) was added to oral GCs initiated at a maximum dose of 60 mg/day, tapered every 2 weeks to 10 mg/day. Propensity score methodology was used to generate two groups of matched patients (n=179) from the ALMS (IVC and MMF) and AURA-LV/AURORA 1 (voclosporin) studies based on the following parameters: age, duration of lupus nephritis, duration of SLE, albumin, C3, C4, creatinine, anti-dsDNA, eGFR, UPCR, biopsy class, sex, and geographical region. Adverse events (AEs) occurred on or after the first dose of study drug up to either 3 or 6 months of treatment and coded by System Organ Class and Preferred Term using MedDRA v9.1 (ALMS), v17.0 (AURA-LV) and v20.0 (AURORA 1). AEs were selected for inclusion in this table to evaluate the impact of IVC, MMF, voclosporin, and glucocorticoids on these organ systems. Assignation of AEs of ‘GFR decreased’ were based on the clinical discretion of the study investigator and were not characterized by a specified drop in eGFR from baseline. GFR, glomerular filtration rate; IVC, intravenous cyclophosphamide; MMF, mycophenolate mofetil.
We report the case of a woman in her 30s who was referred to the ear, nose and throat department with sudden onset left-sided sensorineural hearing loss (SNHL), left anterior uveitis and erythematous ...lower limb lesions with bilateral pitting oedema. Based on her symptoms, an underlying inflammatory systemic disease was suspected. Autoantibodies were negative but an X-ray and high-resolution CT scan of the chest were suggestive of sarcoidosis, which was confirmed on endoscopic bronchial biopsy. Following treatment with a course of oral steroids, the patient's hearing has improved but she still suffers from episodes of uveitis. While immune-mediated inner ear disorders are a recognised cause of SNHL, sarcoidosis is a very rare cause. This case demonstrates the importance of screening for systemic autoimmune aetiology in SNHL and highlights the importance of an effective multidisciplinary team in the diagnosis and management of these patients.
Genome-wide association studies have identified a genetic variant at 3p14.3 (SNP rs1354034) that strongly associates with platelet number and mean platelet volume in humans. While originally proposed ...to be intronic, analysis of mRNA expression in primary human hematopoietic subpopulations reveals that this SNP is located directly upstream of the predominantly expressed ARHGEF3 isoform in megakaryocytes (MK). We found that ARHGEF3, which encodes a Rho guanine exchange factor, is dramatically upregulated during both human and murine MK maturation. We show that the SNP (rs1354034) is located in a DNase I hypersensitive region in human MKs and is an expression quantitative locus (eQTL) associated with ARHGEF3 expression level in human platelets, suggesting that it may be the causal SNP that accounts for the variations observed in human platelet traits and ARHGEF3 expression. In vitro human platelet activation assays revealed that rs1354034 is highly correlated with human platelet activation by ADP. In order to test whether ARHGEF3 plays a role in MK development and/or platelet function, we developed an Arhgef3 KO/LacZ reporter mouse model. Reflecting changes in gene expression, LacZ expression increases during MK maturation in these mice. Although Arhgef3 KO mice have significantly larger platelets, loss of Arhgef3 does not affect baseline MK or platelets nor does it affect platelet function or platelet recovery in response to antibody-mediated platelet depletion compared to littermate controls. In summary, our data suggest that modulation of ARHGEF3 gene expression in humans with a promoter-localized SNP plays a role in human MKs and human platelet function-a finding resulting from the biological follow-up of human genetic studies. Arhgef3 KO mice partially recapitulate the human phenotype.
•Effects of herbivory and nutrients on plant productivity and C storage.•Herbivory enhanced foliar P concentrations but reduced aboveground biomass.•Nitrogen and P enrichment increased N and P stocks ...but not aboveground biomass.
Herbivory and nutrients are major ecosystem drivers in African tropical savanna. Although previous studies have determined the influence of herbivory on carbon storage in savanna ecosystems, little is known about the interactive effects of nutrients and herbivory. We determined the effects of long term grazing and short-term factorial nitrogen (N) and phosphorus (P) additions on aboveground biomass, soil organic matter (SOM) content, and plant nutrient storage. Grazing reduced aboveground biomass, foliar P and N stocks by 45%, 38% and 45%, respectively, compared to ungrazed plots, although the foliar P concentration was 20% greater in grazed plots. There was no significant increase in the aboveground biomass after nutrient addition despite increases in foliar N and P concentrations, suggesting that productivity was limited by a different resource (e.g., moisture). There were no significant interactions between nutrient enrichment and grazing. We conclude that grazing reduced aboveground biomass, but improved grass quality through increased foliar P concentration.
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