The First 500 Registrations to the Research Registry®: Advancing Registration of Under-Registered Study Types

Introduction: The Declaration of Helsinki 2013 encourages the registration of all research studies involving human participants. However, emphasis has been placed on prospective clinical trials, and it is estimated that only 10% of observational studies are registered. In response, Research Registry®1 was launched in February 2015; a retrospectively curated registry that is free and easy to use. Research Registry® enables prospective or retrospective registration of studies, including those study types that cannot be registered on existing registries. In this study, we describe the first 500 registrations on Research Registry®. Methods: Since the launch of Research Registry® in February 2015, data of registrations have been collected, including type of studies registered, country of origin, and data curation activity. Inappropriate registrations, such as duplicates, were identified by the data curation process. These were removed from the database or modified as required. A quality score was assigned for each registration, based on Sir Austin Bradford Hill’s criteria on what research studies should convey. Changes in quality scores over time were assessed. Results: A total of 500 studies were registered on Research Registry® from February 2015 to October 2015, with a total of 1.7 million patients enrolled. The most common study types were retrospective cohort studies (37.2%), case series (14.8%), and first-in-man case reports (10.4%). Registrations were received from 57 different countries; the most submissions were received from Turkey, followed by China and the United Kingdom. Retrospective data curation identified 80 studies that were initially registered as the incorrect study type, and were subsequently correct. The Kruskal–Wallis test identified a significant improvement in quality scores for registrations from February 2015 to October 2015 (p < 0.0001). Conclusions: Since its conception in February 2015, Research Registry® has established itself as a new registry that is free, easy to use, and enables the registration of various study types, including observational studies and first-in-man case reports. Going forward, our plan is to continue developing Research Registry® in line with user feedback and usability studies. We plan to further promote Research Registry® to advance the cause of registration of research, to increase compliance with the Declaration of Helsinki 2013

The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease

Supplementary processed data for Chandler et al. Single-cell transcriptomics identifies aberrant glomerular angiogenic signalling in the early stages of a murine model of WT1 kidney disease

Summary datafiles for Chandler et al. Processed single-cell RNA sequencing data, derived from murine glomeruli (isolated using the dynabead technique) from n = 2 wild-type Wt1+/+ (Ctrl) and n = 2 mutant Wt1R394W/+ (Mut) littermates of WT1 glomerulopathy, followed by 10x Genomics Chromium v3 platform. Please refer to associated scripts for analysis of the data: https://github.com/daniyal-jafree1995/collaborations/blob/main/Chandleretal_2022_WT1glomerulopathyscRNAseq.R File descriptions as below: barcodes.tsv.gz - barcodes file required for input to Read10X function in Seurat features.tsv.gz - features file required for input to Read10X function in Seurat matrix.mtx.gz - matrix file required for input to Read10X function in Seurat WT1_scRNAseq.rds - RDS file containing processed and annotated Seurat object for downstream analysi

Systemic gene therapy with thymosin β4 alleviates glomerular injury in mice

Abstract Plasma ultrafiltration in the kidney occurs across glomerular capillaries, which are surrounded by epithelial cells called podocytes. Podocytes have a unique shape maintained by a complex cytoskeleton, which becomes disrupted in glomerular disease resulting in defective filtration and albuminuria. Lack of endogenous thymosin β4 (TB4), an actin sequestering peptide, exacerbates glomerular injury and disrupts the organisation of the podocyte actin cytoskeleton, however, the potential of exogenous TB4 therapy to improve podocyte injury is unknown. Here, we have used Adriamycin (ADR), a toxin which injures podocytes and damages the glomerular filtration barrier leading to albuminuria in mice. Through interrogating single-cell RNA-sequencing data of isolated glomeruli we demonstrate that ADR injury results in reduced levels of podocyte TB4. Administration of an adeno-associated viral vector encoding TB4 increased the circulating level of TB4 and prevented ADR-induced podocyte loss and albuminuria. ADR injury was associated with disorganisation of the podocyte actin cytoskeleton in vitro, which was ameliorated by treatment with exogenous TB4. Collectively, we propose that systemic gene therapy with TB4 prevents podocyte injury and maintains glomerular filtration via protection of the podocyte cytoskeleton thus presenting a novel treatment strategy for glomerular disease

Spatiotemporal dynamics and heterogeneity of renal lymphatics in mammalian development and cystic kidney disease

Heterogeneity of lymphatic vessels during embryogenesis is critical for organ-specific lymphatic function. Little is known about lymphatics in the developing kidney, despite their established roles in pathology of the mature organ. We performed three-dimensional imaging to characterize lymphatic vessel formation in the mammalian embryonic kidney at single-cell resolution. In mouse, we visually and quantitatively assessed the development of kidney lymphatic vessels, remodeling from a ring-like anastomosis under the nascent renal pelvis, a site of VEGF-C expression, to form a patent vascular plexus. We identified a heterogenous population of lymphatic endothelial cell clusters in mouse and human embryonic kidneys. Exogenous VEGF-C expanded the lymphatic population in explanted mouse embryonic kidneys. Finally, we characterized complex kidney lymphatic abnormalities in a genetic mouse model of polycystic kidney disease. Our study provides novel insights into the development of kidney lymphatic vasculature; a system which likely has fundamental roles in renal development, physiology and disease

Single-cell transcriptomics identifies aberrant glomerular angiogenic signalling in the early stages of WT1 kidney disease

WT1 encodes a podocyte transcription factor whose variants can cause an untreatable glomerular disease in early childhood. Although WT1 regulates many podocyte genes, it is poorly understood which of them are initiators in disease and how they subsequently influence other cell-types in the glomerulus. We hypothesised this could be resolved using single-cell RNA sequencing (scRNA-seq) and ligand-receptor analysis to profile glomerular cell-cell communication during the early stages of disease in mice harbouring an orthologous human mutation in WT1 (Wt1R394W/+). Podocytes were the most dysregulated cell-type in the early stages of Wt1R394W/+ disease, with disrupted angiogenic signalling between podocytes and the endothelium, including the significant downregulation of the vascular factors Vegfa and Neuropilin-1. These signalling changes preceded glomerular endothelial cell loss in advancing disease, a feature also observed in biopsy samples from human WT1 glomerulopathies. Addition of conditioned media from murine Wt1R394W/+ primary podocytes to wild-type glomerular endothelial cells resulted in impaired endothelial looping and reduced vascular complexity. Despite the loss of key angiogenic molecules in Wt1R394W/+ podocytes, the pro-vascular molecule adrenomedullin was upregulated in Wt1R394W/+ podocytes and plasma and its further administration was able to rescue the impaired looping observed when glomerular endothelium were exposed to Wt1R394W/+ podocyte media. In comparative analyses, adrenomedullin upregulation was part of a common injury signature across multiple murine and human glomerular disease datasets, whilst other gene changes were unique to WT1 disease. Collectively, our study describes a novel role for altered angiogenic signalling in the initiation of WT1 glomerulopathy. We also identify adrenomedullin as a proangiogenic factor, which despite being upregulated in early injury, offers an insufficient protective response due to the wider milieu of dampened vascular signalling that results in endothelial cell loss in later disease