Expression of polycomb protein BMI-1 1 maintains the plasticity of basal 2 bronchial epithelial cells

The airway epithelium is altered in respiratory disease and is thought to contribute to disease aetiology. A caveat to disease research is that the technique of isolation of bronchial epithelial cells from patients is invasive and cells have a limited lifespan. The aim of the current study was to extensively characterise the plasticity of primary human bronchial epithelial cells that have been engineered to delay cell senescence including the ability of these cells to differentiate. Cells were engineered to express BMI-1 or hTERT using viral vector systems. Cells were characterised at passage (p) early (p5), mid (p10) and late (p15) stage for; BMI-1, p16 and CK14 protein expression, viability and the ability to differentiate at air-liquid interface (ALI), using a range of techniques including immunohistochemistry (IHC), immunofluorescence (IF), transepithelial electrical resistance (TEER), Scanning Electron Microscopy (SEM), (MUC5AC and beta tubulin (BTUB) staining). BMI-1 expressing cells maintained elevated levels of the BMI-1 protein and the epithelial marker CK14 and showed a suppression of p16. BMI-1 expressing cells had a viability advantage, differentiated at ALI and had a normal karyotype. In contrast hTERT expressing cells had a reduced viability, showed limited differentiation and had an abnormal karyotype. We therefore provide extensive characterisation of the plasticity of BMI-1 expression cells in the context of the ALI model. These cells retain properties of wild-type cells and may be useful to characterise respiratory disease mechanisms in vitro over sustained periods

Team-taught vs sole-taught anatomy practical classes: Enhancing the student learning experience

Practical classes are an integral part of learning human anatomy. The importance of utilising 3-dimensional resources (such as cadavers and skeletons) is only overshadowed by the teacher/student interactions when determining a positive learning experience. As student diversity in Higher Education increases, teaching approaches must also evolve. This study was developed in response to increased student diversity within an anatomy course. It aimed to compare allied health students’ perceptions of anatomy practical classes delivered via two different formats. In 2018, a team-taught format (comprising a lead demonstrator (LD), clinical demonstrator (CD) and near-peer demonstrator (NPD)) was introduced at the large, metropolitan campus, while the smaller regional campus continued the sole-taught format. Student data were collected via anonymous online surveys and interviews. Quantitative data were analysed using ANOVA or appropriate non-parametric testing and qualitative data underwent thematic analysis. Satisfaction scores significantly increased at the team-taught metropolitan campus compared with 2017 when all practical classes were sole taught. Four key themes were realised with the team-taught format: Improved student learning experience; Diverse perspectives; Demonstrator characteristics (Nurturing expert (LD); inspiring clinical contextualiser (CD); relatable study advisor (NPD)); Confidence and approachability. Findings demonstrated that both sole- and team-taught anatomy practical classes can provide students with a positive learning experience; however, a team-taught format of practical classes may provide students with a richer learning experience. The multiple perspectives of different demonstrators were highly valued by students and should be considered as an important approach to teaching students with diverse academic credentials, backgrounds and learning experiences. The interaction between students and teachers is key to instilling motivation and active participation, especially during practical sessions. Stressing key pedagogical (andragogical) principles such as introducing clinical examples and sharing personal experiences can be enhanced if the background of the teaching staff is varied

Developing anatomy demonstrators of the future: The role of team-teaching

ABSTRACT Recent decades have seen cadaveric anatomy teaching decline and shift from traditionally team-taught practicals in large dissection laboratories to sole-taught classes in smaller laboratories. Such changes may alter teaching quality due to loss of peer teacher interactions in class. The current study aimed to compare experiences of team-taught versus sole-taught practicals in the same course across two campuses. This paper presents on the staff experiences. The study utilised educational design research methodology for an iterative approach to solving the problem of optimising cadaveric-based teaching. Classes at the metropolitan campus were team-taught (lead demonstrator, clinical demonstrator and near-peer demonstrator, n=18) and sole-taught at the regional, smaller campus (lead demonstrator only, n=5). Demonstrators completed an anonymous online survey that explored their teaching experiences and thematic analysis of survey data was conducted. Benefits of team-teaching were captured under the themes learn-observe-support, more time with students and catering for student differences. While most team-teaching staff reported no challenges, some noted the need for time to establish effective team dynamics. Sole-teaching staff reported the benefit of consistency in teaching but challenges in providing adequate support to all students. While sole-teaching facilitates consistency in teaching, team-teaching enables staff to develop teaching expertise and anatomical knowledge from interactions with a range of demonstrators during practicals. Team-teaching facilitates knowledge transfer between staff, and this holds important workforce implications for developing anatomy teachers of the future

Randomised controlled trial of the impact of haemodiafiltration on uraemic neuropathy: FINESSE study protocol

Introduction: The majority of patients undergoing haemodialysis (HD) show evidence of uraemic neuropathy, a condition with no known disease-modifying treatments. The pathogenesis of uraemic neuropathy is poorly understood, but may be related to cumulative exposure to middle molecules or other solutes such as potassium. It is not known whether haemodiafiltration (HDF) reduces the progression of uraemic neuropathy. Methods and analysis: Filtration In the Neuropathy of End-Stage kidney disease Symptom Evolution (FINESSE) is a multicentre, randomised, open-label, blinded endpoint assessment, controlled trial designed to assess the impact of HDF versus HD on uraemic neuropathy. Maintenance HD patients will be randomised in a 1:1 ratio to receive HDF or HD with high-flux membranes for 4 years. The primary endpoint is the difference in the mean change in Total Neuropathy Score (TNS) - a measure of peripheral neuropathy combining symptoms, signs and nerve conduction velocity - over the study period. Secondary outcomes include change at annual timepoints in the TNS and the Neuropathy Symptom Score; and in morbidity, mortality and safety events. Ethics and dissemination: The FINESSE trial has been approved by the Ethics Review Committee of the Sydney South West Area Health Service (HREC/09/RPAH/268) and of Adventist HealthCare Limited (2012-027). When published in a peer-reviewed journal, it will be the largest and longest reported randomised trial aimed at reducing the incidence and severity of uraemic neuropathy. It will advance the understanding of the natural history of uraemic neuropathy and the influence of convective therapies on both neurophysiological and clinical outcomes. It will also allow refinement of current hypotheses surrounding the pathogenesis of uraemic neuropathy and, most importantly, may lead to improvements in the lives of the many patients affected by this debilitating condition

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection

Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial

BackgroundSparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis.MethodsPROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin–angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850.FindingsBetween Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6–110) was −2·7 mL/min per 1·73 m2 per year versus −3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1–week 110) was −2·9 mL/min per 1·73 m2 per year versus −3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI −0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (−42·8%, 95% CI −49·8 to −35·0, with sparsentan versus −4·4%, −15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals.InterpretationOver 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics