Podocyte protease activated receptor 1 stimulation in mice produces focal segmental glomerulosclerosis mirroring human disease signaling events.

About 30% of patients who have a kidney transplant with underlying nephrotic syndrome (NS) experience rapid relapse of disease in their new graft. This is speculated to be due to a host-derived circulating factor acting on podocytes, the target cells in the kidney, leading to focal segmental glomerulosclerosis (FSGS). Our previous work suggests that podocyte membrane protease receptor 1 (PAR-1) is activated by a circulating factor in relapsing FSGS. Here, the role of PAR-1 was studied in human podocytes in vitro, and using a mouse model with developmental or inducible expression of podocyte-specific constitutively active PAR-1, and using biopsies from patients with nephrotic syndrome. In vitro podocyte PAR-1 activation caused a pro-migratory phenotype with phosphorylation of the kinase JNK, VASP protein and docking protein Paxillin. This signaling was mirrored in podocytes exposed to patient relapse-derived NS plasma and in patient disease biopsies. Both developmental and inducible activation of transgenic PAR-1 (NPHS2 Cre PAR-1Active+/-) caused early severe nephrotic syndrome, FSGS, kidney failure and, in the developmental model, premature death. We found that the non-selective cation channel protein TRPC6 could be a key modulator of PAR-1 signaling and TRPC6 knockout in our mouse model significantly improved proteinuria and extended lifespan. Thus, our work implicates podocyte PAR-1 activation as a key initiator of human NS circulating factor and that the PAR-1 signaling effects were partly modulated through TRPC6.

Utility of bile acids in large airway bronchial wash versus bronchoalveolar lavage as biomarkers of microaspiration in lung transplant recipients: a retrospective cohort study.

BACKGROUND: Bronchoalveolar lavage (BAL) is a key tool in respiratory medicine for sampling the distal airways. BAL bile acids are putative biomarkers of pulmonary microaspiration, which is associated with poor outcomes after lung transplantation. Compared to BAL, large airway bronchial wash (LABW) samples the tracheobronchial space where bile acids may be measurable at more clinically relevant levels. We assessed whether LABW bile acids, compared to BAL bile acids, are more strongly associated with poor clinical outcomes in lung transplant recipients. METHODS: Concurrently obtained BAL and LABW at 3 months post-transplant from a retrospective cohort of 61 lung transplant recipients were analyzed for taurocholic acid (TCA), glycocholic acid (GCA), and cholic acid by mass spectrometry and 10 inflammatory proteins by multiplex immunoassay. Associations between bile acids with inflammatory proteins and acute lung allograft dysfunction were assessed using Spearman correlation and logistic regression, respectively. Time to chronic lung allograft dysfunction and death were evaluated using multivariable Cox proportional hazards and Kaplan-Meier methods. RESULTS: Most bile acids and inflammatory proteins were higher in LABW than in BAL. LABW bile acids correlated with inflammatory proteins within and between sample type. LABW TCA and GCA were associated with acute lung allograft dysfunction (OR = 1.368; 95%CI = 1.036-1.806; P = 0.027, OR = 1.064; 95%CI = 1.009-1.122; P = 0.022, respectively). No bile acids were associated with chronic lung allograft dysfunction. Adjusted for risk factors, LABW TCA and GCA predicted death (HR = 1.513; 95%CI = 1.014-2.256; P = 0.042, HR = 1.597; 95%CI = 1.078-2.366; P = 0.020, respectively). Patients with LABW TCA in the highest tertile had worse survival compared to all others. CONCLUSIONS: LABW bile acids are more strongly associated than BAL bile acids with inflammation, acute lung allograft dysfunction, and death in lung transplant recipients. Collection of LABW may be useful in the evaluation of microaspiration in lung transplantation and other respiratory diseases.

COVID-19 vaccination in children and adolescents aged 5 years and older undergoing treatment for cancer and non-malignant haematological conditions: Australian and New Zealand Children's Haematology/Oncology Group consensus statement.

INTRODUCTION: The Australian Technical Advisory Group on Immunisation and New Zealand Ministry of Health recommend all children aged ≥ 5 years receive either of the two mRNA COVID-19 vaccines: Comirnaty (Pfizer), available in both Australia and New Zealand, or Spikevax (Moderna), available in Australia only. Both vaccines are efficacious and safe in the general population, including children. Children and adolescents undergoing treatment for cancer and immunosuppressive therapy for non-malignant haematological conditions are particularly vulnerable, with an increased risk of severe or fatal COVID-19. There remains a paucity of data regarding the immune response to COVID-19 vaccines in immunosuppressed paediatric populations, with data suggestive of reduced immunogenicity of the vaccine in immunocompromised adults. RECOMMENDATIONS: Considering the safety profile of mRNA COVID-19 vaccines and the increased risk of severe COVID-19 in immunocompromised children and adolescents, COVID-19 vaccination is strongly recommended for this at-risk population. We provide a number of recommendations regarding COVID-19 vaccination in this population where immunosuppressive, chemotherapeutic and/or targeted biological agents are used. These include the timing of vaccination in patients undergoing active treatment, management of specific situations where vaccination is contraindicated or recommended under special precautions, and additional vaccination recommendations for severely immunocompromised patients. Finally, we stress the importance of upcoming clinical trials to identify the safest and most efficacious vaccination regimen for this population. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: This consensus statement provides recommendations for COVID-19 vaccination in children and adolescents aged ≥ 5 years with cancer and immunocompromising non-malignant haematological conditions, based on evidence, national and international guidelines and expert opinion. ENDORSED BY: The Australian and New Zealand Children's Haematology/Oncology Group.

Evaluation of Genome Sequences of the Bacteriophages JeTaime and Luna22.

The mycobacteriophages JeTaime (E cluster) and Luna22 (Q cluster) were isolated from soil in Providence, Rhode Island, and Charleston, South Carolina, respectively, using a Mycobacterium smegmatis mc2 155 host. The genome of JeTaime is 75,099 bp (142 predicted genes), and that of Luna22 is 53,730 bp (87 predicted genes). Both phages exhibit Siphoviridae morphology.

Communication and ethical considerations for fertility preservation for patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Patients with childhood, adolescent, and young adult cancer who will be treated with gonadotoxic therapies are at increased risk for infertility. Many patients and their families desire biological children but effective communication about treatment-related infertility risk and procedures for fertility preservation does not always happen. The PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the literature and developed a clinical practice guideline that provides recommendations for ongoing communication methods for fertility preservation for patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger and their families. Moreover, the guideline panel formulated considerations of the ethical implications that are associated with these procedures. Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the evidence and recommendations. In this clinical practice guideline, existing evidence and international expertise are combined to develop transparent recommendations that are easy to use to facilitate ongoing communication between health-care providers and patients with childhood, adolescent, and young adult cancer who might be at high risk for fertility impairment and their families.

Bronchoalveolar bile acid and inflammatory markers to identify high-risk lung transplant recipients with reflux and microaspiration.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a risk factor for chronic lung allograft dysfunction. Bile acids-putative markers of gastric microaspiration-and inflammatory proteins in the bronchoalveolar lavage (BAL) have been associated with chronic lung allograft dysfunction, but their relationship with GERD remains unclear. Although GERD is thought to drive chronic microaspiration, the selection of patients for anti-reflux surgery lacks precision. This multicenter study aimed to test the association of BAL bile acids with GERD, lung inflammation, allograft function, and anti-reflux surgery. METHODS: We analyzed BAL obtained during the first post-transplant year from a retrospective cohort of patients with and without GERD, as well as BAL obtained before and after Nissen fundoplication anti-reflux surgery from a separate cohort. Levels of taurocholic acid (TCA), glycocholic acid, and cholic acid were measured using mass spectrometry. Protein markers of inflammation and injury were measured using multiplex assay and enzyme-linked immunosorbent assay. RESULTS: At 3 months after transplantation, TCA, IL-1ß, IL-12p70, and CCL5 were higher in the BAL of patients with GERD than in that of no-GERD controls. Elevated TCA and glycocholic acid were associated with concurrent acute lung allograft dysfunction and inflammatory proteins. The BAL obtained after anti-reflux surgery contained reduced TCA and inflammatory proteins compared with that obtained before anti-reflux surgery. CONCLUSIONS: Targeted monitoring of TCA and selected inflammatory proteins may be useful in lung transplant recipients with suspected reflux and microaspiration to support diagnosis and guide therapy. Patients with elevated biomarker levels may benefit most from anti-reflux surgery to reduce microaspiration and allograft inflammation.