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The unprecedented demand placed on healthcare systems from the COVID-19 pandemic has forced a reassessment of clinical trial conduct and feasibility. Consequently, the Australasian Kidney Trials Network (AKTN), an established collaborative research group known for conducting investigator-initiated global clinical trials, had to efficiently respond and adapt to the changing landscape during COVID-19. Key priorities included ensuring patient and staff safety, trial integrity and network sustainability for the kidney care community. New resources have been developed to enable a structured review and contingency plan of trial activities during the pandemic and beyond. [ABSTRACT FROM AUTHOR]

Background/Aims: Cardiac biomarkers are associated with cardiac abnormalities and adverse outcomes in dialysis patients. Our aim was to report the effect of the beta-blocker carvedilol on cardiac biomarkers in adult dialysis patients. Methods: The Beta-Blocker to Lower Cardiovascular Dialysis Events Feasibility Study was a randomized controlled trial comparing carvedilol to placebo. Serum and plasma were collected before the run-in, then 6 and 12 months post-randomization to measure B-type Natriuretic Peptide (BNP), N-terminal BNP (NT-ProBNP), high-sensitivity cardiac troponins I (hs-TnI) and T (hs-TnT), and galectin-3. Left ventricular global longitudinal strain (GLS) was measured by echocardiography at baseline. Results: Seventy-two participants were recruited of whom 49 completed the run-in and were randomized to carvedilol (n=26) or placebo (n=23). Baseline echocardiography demonstrated median (inter-quartile range) GLS of -14.27% (-16.63 to -11.93). NTproBNP and hs-TnT correlated with GLS (Spearman's rho=0.34 [p=0.018] and rho=0.28 [p=0.049], respectively). Median change scores from baseline to 12 months did not differ significantly between participants with complete biomarker data randomized to carvedilol (n=15) or placebo (n=16) for any biomarkers. Conclusions: NT-proBNP and hs-TnT were associated with GLS. However, changes in levels of the biomarkers from baseline to 12 months were not different between groups randomized to carvedilol and placebo. [ABSTRACT FROM AUTHOR]

Background Pentoxifylline has been shown to increase haemoglobin levels in patients with chronic kidney disease (CKD) and erythropoietin-stimulating agent (ESA)-hyporesponsive anaemia in the Handling Erythropoietin Resistance with Oxpentifylline multicentre double-blind, randomized controlled trial. The present sub-study evaluated the effects of pentoxifylline on the iron-regulatory hormone hepcidin in patients with ESA-hyporesponsive CKD. Methods This sub-study included 13 patients in the pentoxifylline arm (400 mg daily) and 13 in the matched placebo arm. Hepcidin-25 was measured by ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry following isolation from patient serum. Serum hepcidin-25, serum iron biomarkers, haemoglobin and ESA dosage were compared within and between the two groups. Results Hepcidin-25 concentration at 4 months adjusted for baseline did not differ significantly in pentoxifylline versus placebo treated patients (adjusted mean difference (MD) −7.9 nmol, P = 0.114), although the difference between the groups mean translated into a >25% reduction of circulating hepcidin-25 due to pentoxifylline compared with the placebo baseline. In paired analysis, serum hepcidin-25 levels were significantly decreased at 4 months compared with baseline in the pentoxifylline group (−5.47 ± 2.27 nmol/l, P < 0.05) but not in the placebo group (2.82 ± 4.29 nmol/l, P = 0.24). Pentoxifylline did not significantly alter serum ferritin (MD 55.4 mcg/l), transferrin saturation (MD 4.04%), the dosage of ESA (MD −9.93 U/kg per week) or haemoglobin concentration (MD 5.75 g/l). Conclusion The reduction of circulating hepcidin-25 due to pentoxifylline did not reach statistical significance; however, the magnitude of the difference suggests that pentoxifylline may be a clinically and biologically meaningful modulator of hepcidin-25 in dialysis of patients with ESA-hyporesponsive anaemia. [ABSTRACT FROM AUTHOR]

Objective: Pentoxifylline has previously been shown to increase haemoglobin levels in patients with chronic kidney disease (CKD) and erythropoietin-stimulating agent (ESA)-hyporesponsive anaemia in the HERO multi-centre double-blind, randomized controlled trial. The present study evaluated the effects of pentoxifylline on oxidative stress in ESA-hyporesponsive CKD patients. Methods: This sub-study of the HERO trial compared 15 patients in the pentoxifylline arm (400 mg daily) and 17 in the matched placebo arm on oxidative stress markers: plasma total F2-isoprostanes, protein carbonyls, glutathione peroxidase (GPX), and superoxide dismutase (SOD) activities. Results: Pentoxifylline did not significantly alter total F2-isoprostanes (adjusted mean difference (MD) 35.01 pg/ml,P = 0.11), SOD activity (MD 0.82 U/ml,P = 0.07), GPX activity (MD −6.06 U/l,P = 0.09), or protein carbonyls (MD −0.04 nmol/mg,P = 0.52). Replicating results from the main study, pentoxifylline significantly increased haemoglobin concentration compared with controls (MD 7.2 g/l,P = 0.04). Conclusions: Pentoxifylline did not alter oxidative stress biomarkers, suggesting that alternative mechanisms may be responsible for the agent's ability to augment haemoglobin levels in CKD patients with ESA-hyporesponsive anaemia. [ABSTRACT FROM AUTHOR]

Perturbations of the p53 pathway are associated with more aggressive and therapeutically refractory tumors. However, molecular assessment of p53 status, by using sequence analysis and immunohistochemistry, are incomplete assessors of p53 functional effects. We posited that the transcriptional fingerprint is a more definitive downstream indicator of p53 function. Herein, we analyzed transcript profiles of 251 p53-sequenced primary breast tumors and identified a clinically embedded 32-gene expression signature that distinguishes p53-mutant and wild-type tumors of different histologies and outperforms sequence-based assessments of p53 in predicting prognosis and therapeutic response. Moreover, the p53 signature identified a subset of aggressive tumors absent of sequence mutations in p53 yet exhibiting expression characteristics consistent with p53 deficiency because of attenuated p53 transcript levels. Our results show the primary importance of p53 functional status in predicting clinical breast cancer behavior. [ABSTRACT FROM AUTHOR]

Unlabelled: ♦, Background: The HONEYPOT study recently reported that daily exit-site application of antibacterial honey was not superior to nasal mupirocin prophylaxis for preventing overall peritoneal dialysis (PD)-related infection. This paper reports a secondary outcome analysis of the HONEYPOT study with respect to exit-site infection (ESI) and peritonitis microbiology, infectious hospitalization and technique failure. ♦, Methods: A total of 371 PD patients were randomized to daily exit-site application of antibacterial honey plus usual exit-site care (N = 186) or intranasal mupirocin prophylaxis (in nasal Staphylococcus aureus carriers only) plus usual exit-site care (control, N = 185). Groups were compared on rates of organism-specific ESI and peritonitis, peritonitis- and infection-associated hospitalization, and technique failure (PD withdrawal). ♦, Results: The mean peritonitis rates in the honey and control groups were 0.41 (95% confidence interval [CI] 0.32 - 0.50) and 0.41 (95% CI 0.33 - 0.49) episodes per patient-year, respectively (incidence rate ratio [IRR] 1.01, 95% CI 0.75 - 1.35). When specific causative organisms were examined, no differences were observed between the groups for gram-positive (IRR 0.99, 95% CI 0.66 - 1.49), gram-negative (IRR 0.71, 95% CI 0.39 - 1.29), culture-negative (IRR 2.01, 95% CI 0.91 - 4.42), or polymicrobial peritonitis (IRR 1.08, 95% CI 0.36 - 3.20). Exit-site infection rates were 0.37 (95% CI 0.28 - 0.45) and 0.33 (95% CI 0.26 - 0.40) episodes per patient-year for the honey and control groups, respectively (IRR 1.12, 95% CI 0.81 - 1.53). No significant differences were observed between the groups for gram-positive (IRR 1.10, 95% CI 0.70 - 1.72), gram-negative (IRR: 0.85, 95% CI 0.46 - 1.58), culture-negative (IRR 1.88, 95% CI 0.67 - 5.29), or polymicrobial ESI (IRR 1.00, 95% CI 0.40 - 2.54). Times to first peritonitis-associated and first infection-associated hospitalization were similar in the honey and control groups. The rates of technique failure (PD withdrawal) due to PD-related infection were not significantly different between the groups. ♦, Conclusion: Compared with standard nasal mupirocin prophylaxis, daily topical exit-site application of antibacterial honey resulted in comparable rates of organism-specific peritonitis and ESI, infection-associated hospitalization, and infection-associated technique failure in PD patients., (Copyright © 2015 International Society for Peritoneal Dialysis.)

Background: Estrogens and their receptors are important in human development, physiology and disease. In this study, we utilized an integrated genome-wide molecular and computational approach to characterize the interaction between the activated estrogen receptor (ER) and the regulatory elements of candidate target genes., Results: Of around 19,000 genes surveyed in this study, we observed 137 ER-regulated genes in T-47D cells, of which only 89 were direct target genes. Meta-analysis of heterogeneous in vitro and in vivo datasets showed that the expression profiles in T-47D and MCF-7 cells are remarkably similar and overlap with genes differentially expressed between ER-positive and ER-negative tumors. Computational analysis revealed a significant enrichment of putative estrogen response elements (EREs) in the cis-regulatory regions of direct target genes. Chromatin immunoprecipitation confirmed ligand-dependent ER binding at the computationally predicted EREs in our highest ranked ER direct target genes, NRIP1, GREB1 and ABCA3. Wider examination of the cis-regulatory regions flanking the transcriptional start sites showed species conservation in mouse-human comparisons in only 6% of predicted EREs., Conclusions: Only a small core set of human genes, validated across experimental systems and closely associated with ER status in breast tumors, appear to be sufficient to induce ER effects in breast cancer cells. That cis-regulatory regions of these core ER target genes are poorly conserved suggests that different evolutionary mechanisms are operative at transcriptional control elements than at coding regions. These results predict that certain biological effects of estrogen signaling will differ between mouse and human to a larger extent than previously thought.