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Endomyocardial biopsies (EMB) gene expression profiling is a promising companion tool for rejection diagnosis. Targeted molecular profiling combined with reproducible formalin-fixed paraffin-embedded (FFPE) EMB-based technology has the potential to change the current paradigm of cardiac rejection diagnosis. We aimed to develop and validate targeted gene expression diagnostic models of cardiac rejection. We performed a multicenter, retrospective study, building a reference set of 610 FFPE-EMB collected between 2011 and 2021 and representative of the landscape of rejection (antibody-mediated rejection-AMR, n=189; acute cellular rejection-ACR, n=289; non-rejection, n=114). Nanostring nCounter technology with BHOT panel, a targeted consensus panel of 770 genes, was used to analyze tissue gene expression. Differential expression and elastic net approach were applied to identify key AMR and ACR-related transcripts. An ensemble model was used to build molecular classifiers of AMR and ACR. Their performance was evaluated in an independent validation set (n=117). Overall, the molecular analysis of 592 (97%) biopsies successfully passed all quality control and normalization steps. The molecular profiles of both ACR and AMR included typical transcripts reflecting the rejection-related pathophysiology. In the validation cohort, the AMR and ACR models accurately identified rejection. The diagnostic accuracy was 81.89% for AMR (ROC-AUC=0.844, Brier score=0.143) and 77.58% for ACR (ROC-AUC=0.812, Brier score=0.176). Principal component analysis based on the molecular scores showed the detection of 72% of variance (Figure) allowing the histo-molecular contextualization of the reference set samples according to the molecular scores. Applying a targeted gene set on FFPE EMB, we developed robust molecular-based models of cardiac rejection, showing high diagnostic accuracy for pathology-defined diagnoses. [ABSTRACT FROM AUTHOR]

Recently, interest in transcriptomic assessment of kidney biopsies has been growing. This study investigates the use of NGS to identify gene expression changes and analyse the pathways involved in rejection. An Illumina bulk RNA sequencing on the polyadenylated RNA of 770 kidney biopsies was conducted. Differentially-expressed genes (DEGs) were determined for AMR and TCMR using DESeq2. Genes were segregated according to their previous descriptions in known panels (microarray or the Banff Human Organ Transplant (B-HOT) panel) to obtain NGS-specific genes. Pathway enrichment analysis was performed using the Reactome and Kyoto Encyclopaedia of Genes and Genomes (KEGG) public repositories. The differential gene expression using NGS analysis identified 6,141 and 8,478 transcripts associated with AMR and TCMR. While most of the genes identified were included in the microarray and the B-HOT panels, NGS analysis identified 603 (9.8%) and 1,186 (14%) new specific genes. Pathways analysis showed that the B-HOT panel was associated with the main immunological processes involved during AMR and TCMR. The microarrays specifically integrated metabolic functions and cell cycle progression processes. Novel NGS-specific based transcripts associated with AMR and TCMR were discovered, which might represent a novel source of targets for drug designing and repurposing., Competing Interests: Author PG was employed by GenoSplice. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cortes Garcia, Giarraputo, Racapé, Goutaudier, Ursule-Dufait, de la Grange, Adoux, Raynaud, Couderau, Mezine, Dagobert, Bestard, Moreso, Villard, Halleck, Giral, Brouard, Danger, Gourraud, Rabant, Couzi, Le Quintrec, Kamar, Morelon, Vrtovsnik, Taupin, Snanoudj, Legendre, Anglicheau, Budde, Lefaucheur, Loupy and Aubert.)

Background: The COVID-19 pandemic has severely affected health systems and medical research worldwide but its impact on the global publication dynamics and non-COVID-19 research has not been measured. We hypothesized that the COVID-19 pandemic may have impacted the scientific production of non-COVID-19 research., Methods: We conducted a comprehensive meta-research on studies (original articles, research letters and case reports) published between 01/01/2019 and 01/01/2021 in 10 high-impact medical and infectious disease journals (New England Journal of Medicine, Lancet, Journal of the American Medical Association, Nature Medicine, British Medical Journal, Annals of Internal Medicine, Lancet Global Health, Lancet Public Health, Lancet Infectious Disease and Clinical Infectious Disease). For each publication, we recorded publication date, publication type, number of authors, whether the publication was related to COVID-19, whether the publication was based on a case series, and the number of patients included in the study if the publication was based on a case report or a case series. We estimated the publication dynamics with a locally estimated scatterplot smoothing method. A Natural Language Processing algorithm was designed to calculate the number of authors for each publication. We simulated the number of non-COVID-19 studies that could have been published during the pandemic by extrapolating the publication dynamics of 2019 to 2020, and comparing the expected number to the observed number of studies., Results: Among the 22,525 studies assessed, 6319 met the inclusion criteria, of which 1022 (16.2%) were related to COVID-19 research. A dramatic increase in the number of publications in general journals was observed from February to April 2020 from a weekly median number of publications of 4.0 (IQR: 2.8-5.5) to 19.5 (IQR: 15.8-24.8) (p < 0.001), followed afterwards by a pattern of stability with a weekly median number of publications of 10.0 (IQR: 6.0-14.0) until December 2020 (p = 0.045 in comparison with April). Two prototypical editorial strategies were found: 1) journals that maintained the volume of non-COVID-19 publications while integrating COVID-19 research and thus increased their overall scientific production, and 2) journals that decreased the volume of non-COVID-19 publications while integrating COVID-19 publications. We estimated using simulation models that the COVID pandemic was associated with a 18% decrease in the production of non-COVID-19 research. We also found a significant change of the publication type in COVID-19 research as compared with non-COVID-19 research illustrated by a decrease in the number of original articles, (47.9% in COVID-19 publications vs 71.3% in non-COVID-19 publications, p < 0.001). Last, COVID-19 publications showed a higher number of authors, especially for case reports with a median of 9.0 authors (IQR: 6.0-13.0) in COVID-19 publications, compared to a median of 4.0 authors (IQR: 3.0-6.0) in non-COVID-19 publications (p < 0.001)., Conclusion: In this meta-research gathering publications from high-impact medical journals, we have shown that the dramatic rise in COVID-19 publications was accompanied by a substantial decrease of non-COVID-19 research. META-RESEARCH REGISTRATION: https://osf.io/9vtzp/ ., (© 2021. The Author(s).)

The development of new high-throughput technologies in genomics and then in transcriptomics has modified clinical approach in nephrology. At the interface between high-throughput technologies (microarray, new generation sequencing «NGS») and few mRNA analysis (reverse transcriptase quantitative PCR [RT-qPCR]), the nCounter® of NanoString® offers a new and complementary approach. Capable of analyzing formalin-fixed paraffin-embedded samples, this technology is a credible candidate for implanting transcriptomics in clinical routine., (Copyright © 2020 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.)

This meeting report from the XV Banff conference describes the creation of a multiorgan transplant gene panel by the Banff Molecular Diagnostics Working Group (MDWG). This Banff Human Organ Transplant (B-HOT) panel is the culmination of previous work by the MDWG to identify a broadly useful gene panel based on whole transcriptome technology. A data-driven process distilled a gene list from peer-reviewed comprehensive microarray studies that discovered and validated their use in kidney, liver, heart, and lung transplant biopsies. These were supplemented by genes that define relevant cellular pathways and cell types plus 12 reference genes used for normalization. The 770 gene B-HOT panel includes the most pertinent genes related to rejection, tolerance, viral infections, and innate and adaptive immune responses. This commercially available panel uses the NanoString platform, which can quantitate transcripts from formalin-fixed paraffin-embedded samples. The B-HOT panel will facilitate multicenter collaborative clinical research using archival samples and permit the development of an open source large database of standardized analyses, thereby expediting clinical validation studies. The MDWG believes that a pathogenesis and pathway based molecular approach will be valuable for investigators and promote therapeutic decision-making and clinical trials., (© 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)