Visual statistical learning alters low-dimensional cortical architecture.

Our brains are in a constant state of generating predictions, implicitly extracting environmental regularities to support later cognition and behavior, a process known as statistical learning (SL). While prior work investigating the neural basis of SL has focused on the activity of single brain regions in isolation, much less is known about how distributed brain areas coordinate their activity to support such learning. Using fMRI and a classic visual SL task, we investigated changes in whole-brain functional architecture as human female and male participants implicitly learned to associate pairs of images, and later, when predictions generated from learning were violated.

Rare disease gene association discovery in the 100,000 Genomes Project.

Up to 80% of rare disease patients remain undiagnosed after genomic sequencing, with many probably involving pathogenic variants in yet to be discovered disease-gene associations. To search for such associations, we developed a rare variant gene burden analytical framework for Mendelian diseases, and applied it to protein-coding variants from whole-genome sequencing of 34,851 cases and their family members recruited to the 100,000 Genomes Project. A total of 141 new associations were identified, including five for which independent disease-gene evidence was recently published.

The impact of a secondary, rare, non-pathogenic PKD1 variant on disease progression in autosomal dominant polycystic kidney disease.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is caused primarily by pathogenic variants in the PKD1 and PKD2 genes. Although the type of ADPKD variant can influence disease severity, rare, hypomorphic PKD1 variants have also been reported to modify disease severity or cause biallelic ADPKD. This study examines whether rare, additional, potentially protein-altering, non-pathogenic PKD1 variants contribute to ADPKD phenotypic outcomes.

Scoping Review of Economic Analyses of Rare Kidney Diseases.

Introduction: Rare kidney diseases (RKDs) place a substantial economic burden on patients and health systems, the extent of which is unknown and may be systematically underestimated by health economic techniques. We aimed to investigate the economic burden and cost-effectiveness evidence base for RKDs.

Methods: We conducted a systematic scoping review to identify economic evaluations, health technology assessments, and cost-of-illness studies relating to RKDs, published since 2012.

SGLT2-Inhibition in Patients With Alport Syndrome.

Introduction: Large-scale trials showed positive outcomes of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in adults with chronic kidney disease (CKD). Whether the use of SGLT2i is safe and effective in patients with the common hereditary CKD Alport syndrome (AS) has not yet been investigated specifically in larger cohorts.

Methods: This observational, multicenter, international study (NCT02378805) assessed 112 patients with AS after start of SGLT2i.

Diagnosis, management and treatment of the Alport syndrome - 2024 guideline on behalf of ERKNet, ERA and ESPN.

Glomerular nephropathy resulting from the genetic defects in COL4A3/4/5 genes including the classical Alport syndrome (AS) is the second commonest hereditary kidney disease characterized by persistent haematuria progressing to the need of kidney replacement therapy, frequently associated with sensorineural deafness, and occasionally with ocular anomalies. Diagnosis and management of COL4A3/4/5 glomerulopathy is a great challenge due to its phenotypic heterogeneity, multiple modes of inheritance, variable expressivity, and disease penetrance of individual variants as well as imperfect prognostic and progression factors and scarce and limited clinical trials, especially in children. As a joint initiative of the European Rare Kidney disease reference Network (ERKNet), European Renal Association (ERA Genes&Kidney) and European Society for Paediatric Nephrology (ESPN) Working Group Hereditary Kidney Disorders, a team of experts including adult and paediatric nephrologists, kidney geneticists, audiologists, ophthalmologists and a kidney pathologist were selected to perform a systematic literature review on 21 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions.

Distinct patterns of connectivity with the motor cortex reflect different components of sensorimotor learning.

Sensorimotor learning is supported by multiple competing processes that operate concurrently, making it a challenge to elucidate their neural underpinnings. Here, using human functional MRI, we identify 3 distinct axes of connectivity between the motor cortex and other brain regions during sensorimotor adaptation. These 3 axes uniquely correspond to subjects' degree of implicit learning, performance errors and explicit strategy use, and involve different brain networks situated at increasing levels of the cortical hierarchy.

Quantifying variant contributions in cystic kidney disease using national-scale whole-genome sequencing.

BACKGROUNDCystic kidney disease (CyKD) is a predominantly familial disease in which gene discovery has been led by family-based and candidate gene studies, an approach that is susceptible to ascertainment and other biases.METHODSUsing whole-genome sequencing data from 1,209 cases and 26,096 ancestry-matched controls participating in the 100,000 Genomes Project, we adopted hypothesis-free approaches to generate quantitative estimates of disease risk for each genetic contributor to CyKD, across genes, variant types and allelic frequencies.RESULTSIn 82.

Description and Cross-Sectional Analyses of 25,880 Adults and Children in the UK National Registry of Rare Kidney Diseases Cohort.

Introduction: The National Registry of Rare Kidney Diseases (RaDaR) collects data from people living with rare kidney diseases across the UK, and is the world's largest, rare kidney disease registry. We present the clinical demographics and renal function of 25,880 prevalent patients and sought evidence of bias in recruitment to RaDaR.

Methods: RaDaR is linked with the UK Renal Registry (UKRR, with which all UK patients receiving kidney replacement therapy [KRT] are registered).

Reconfigurations of cortical manifold structure during reward-based motor learning.

Adaptive motor behavior depends on the coordinated activity of multiple neural systems distributed across the brain. While the role of sensorimotor cortex in motor learning has been well established, how higher-order brain systems interact with sensorimotor cortex to guide learning is less well understood. Using functional MRI, we examined human brain activity during a reward-based motor task where subjects learned to shape their hand trajectories through reinforcement feedback.

Developing Therapies for C3 Glomerulopathy: Report of the Kidney Health Initiative C3 Glomerulopathy Trial Endpoints Work Group.

Randomized clinical trials are underway to evaluate the efficacy of novel agents targeting the alternative complement pathway in patients with C3 glomerulopathy (C3G), a rare glomerular disease. The Kidney Health Initiative convened a panel of experts in C3G to ( 1 ) assess the data supporting the use of the prespecified trial end points as measures of clinical benefit and ( 2 ) opine on efficacy findings they would consider compelling as treatment(s) of C3G in native kidneys. Two subpanels of the C3G Trial Endpoints Work Group reviewed the available evidence and uncertainties for the association between the three prespecified end points-( 1 ) proteinuria, ( 2 ) eGFR, and ( 3 ) histopathology-and anticipated outcomes.

A Randomized Controlled Clinical Trial Testing Effects of Lademirsen on Kidney Function Decline in Adults with Alport Syndrome.

Key Points: Lademirsen, an anti–microRNA-21 therapy, was generally well-tolerated in adults with Alport syndrome at risk of rapid disease progression. There were no significant differences between lademirsen-treated and placebo-treated participants in eGFR at any timepoint. The proportions of participants with prespecified reductions in eGFR at weeks 24 and 48 were not significantly different for lademirsen versus placebo.

Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort.

Background: Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure.

Methods: People aged 0-96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities.

A Neanderthal haplotype introgressed into the human genome confers protection against membranous nephropathy.

Class 2 HLA and PLA2R1 alleles are exceptionally strong genetic risk factors for membranous nephropathy (MN), leading, through an unknown mechanism, to a targeted autoimmune response. Introgressed archaic haplotypes (introduced from an archaic human genome into the modern human genome) might influence phenotypes through gene dysregulation. Here, we investigated the genomic region surrounding the PLA2R1 gene.

Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data.

To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited to the 100,000 Genomes Project (100KGP). Following triaging of the results, 88 novel associations were identified including 38 with existing experimental evidence. We have published the confirmation of one of these associations, hereditary ataxia with , and independent confirmatory evidence has recently been published for four more.

Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy.

Introduction: We reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of patients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells.

Methods: This study was a double-blind, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized to receive placebo, fostamatinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors.

Genetic Modifiers of Mendelian Monogenic Collagen IV Nephropathies in Humans and Mice.

Familial hematuria is a clinical sign of a genetically heterogeneous group of conditions, accompanied by broad inter- and intrafamilial variable expressivity. The most frequent condition is caused by pathogenic (or likely pathogenic) variants in the collagen-IV genes, . Pathogenic variants in are responsible for the severe X-linked glomerulopathy, Alport syndrome (AS), while homozygous or compound heterozygous variants in the or the gene cause autosomal recessive AS.

Common Risk Variants in Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome.

Introduction: Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of kidney disease in children worldwide. Genome-wide association studies (GWAS) have demonstrated the association of SSNS with genetic variation at and have identified several non- loci that aid in further understanding of disease pathophysiology. We sought to identify additional genetic loci associated with SSNS in children of Sri Lankan and European ancestry.

Rare variants in the sodium-dependent phosphate transporter gene SLC34A3 explain missing heritability of urinary stone disease.

Urinary stone disease (USD) is a major health burden affecting over 10% of the United Kingdom population. While stone disease is associated with lifestyle, genetic factors also strongly contribute. Common genetic variants at multiple loci from genome-wide association studies account for 5% of the estimated 45% heritability of the disorder.

Genomics in the kidney clinic.

Inherited diseases are a frequent cause of end-stage kidney disease and often seen in the kidney clinic. Clinical genomic testing is increasingly available in the UK and eligible patients in England can be referred through the NHS Genomic Medicine Service. Testing is useful for diagnosis, prognostication and management of conditions such as autosomal dominant polycystic kidney disease (ADPKD), Alport syndrome, autosomal dominant tubulointerstitial kidney disease (ADTKD) and focal segmental glomerulosclerosis (FSGS).