Abstract
BACKGROUND AND AIMS
UMOD is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is the most abundant protein in urine and ...related to chronic kidney disease, hypertension and pathogen defense. Through basolateral release from kidney epithelial cells, uromodulin also reaches the blood, where its function is largely unknown. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin in seven cohorts using two complementary assays.
METHOD
Separate genome-wide association study meta-analyses for circulating uromodulin were conducted for the antibody-based assay (five cohorts, N = 13 985) and the aptamer-based SOMAscan assay (two cohorts, N = 18 070). Genome-wide significant loci were placed into their functional genomic context using RNA-seq, ATAC-seq and Hi-C data generated from primary human kidney tissue. An array of downstream genetic analyses was then performed for significant loci, including fine-mapping, colocalization analyses and gene-by-gene interaction analyses. The B4GALNT2 p.Cys466Arg allele was expressed in MDCK cells and studied by immunofluorescence and Western blotting analyses.
RESULTS
We detected and replicated 13 genome-wide significant loci (P <5e−8; 12 novel). At the UMOD locus, functional genomics data of primary human kidney tissue highlighted an upstream regulatory variant with differential accessibility and UMOD transcription in uromodulin-synthesizing kidney cells. Shared association patterns with complex traits, including chronic kidney disease and blood pressure, placed the PRKAG2 locus in the same context as UMOD. Experimental validation of another locus, B4GALNT2, showed that the detected p.Cys466Arg variant of the encoded N-acetylgalactosaminyltransferase has a loss-of-function effect leading to higher serum uromodulin levels. Lastly, our results point to enzymes writing glycan marks present on uromodulin and to their receptors in the circulation.
CONCLUSION
This study provides human genetic evidence of new pathway members of uromodulin and delivers novel insights into its determinants and systemic role in the circulation.
Uromodulin (UMOD) is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is highly abundant in urine and related to chronic kidney ...disease, hypertension, and pathogen defense. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin using complementary antibody-based and aptamer-based assays. We detected 3 and 10 distinct significant loci, respectively. Integration of antibody-based results at the UMOD locus with functional genomics data (RNA-Seq, ATAC-Seq, Hi-C) of primary human kidney tissue highlighted an upstream variant with differential accessibility and transcription in uromodulin-synthesizing kidney cells as underlying the observed cis effect. Shared association patterns with complex traits, including chronic kidney disease and blood pressure, placed the PRKAG2 locus in the same pathway as UMOD. Experimental validation of the third antibody-based locus, B4GALNT2, showed that the p.Cys466Arg variant of the encoded N-acetylgalactosaminyltransferase had a loss-of-function effect leading to higher serum uromodulin levels. Aptamer-based results pointed to enzymes writing glycan marks present on uromodulin and to their receptors in the circulation, suggesting that this assay permits investigating uromodulin's complex glycosylation rather than its quantitative levels. Overall, our study provides insights into circulating uromodulin and its emerging functions.
Advances in the development of Direct-Acting Antivirals (DAAs), particularly pangenotypic drugs, have led to a high rate of hepatitis C virus (HCV) eradication. Notably, real- world studies have ...confirmed the efficacy and safety of pangenotypic DAA combinations reported in registration trials. The aim of this study was to review the treatment recommendations, and the efficacy and safety data of anti-HCV pangenotypic drugs reported in registration clinical trials and in recent real-life cohort studies.
We reviewed the efficacy and safety data of pangenotypic anti-HCV drug combinations reported in original articles and in online conference abstracts.
Current pangenotypic drug combinations resulted in very high rates of sustained virologic response and few adverse reactions in real-life settings. SVR12 rates in real-life studies ranged from 90-100% depending on the pangenotypic combination, the HCV genotype and the stage of liver disease. Most adverse reactions reported in real-life settings were mild in intensity and rarely led to treatment discontinuation. These results are in accordance with those of clinical trials.
Pangenotypic DAAs result in very high rates of sustained virologic responses and are well tolerated. However, they are contraindicated in patients with decompensated cirrhosis or advanced chronic kidney disease who failed previous DDA-based treatment. Further research is required to customize treatment to "unpackage" current DAA combinations and to develop generic drugs against HCV.
More than half of the European population live in small and medium size municipalities, where climate adaptation planning is an under-researched topic within the climate change field. Many ...constraints might hinder the implementation of adaptation pilot projects due to lack of economic, knowledge, and technical available resources. Local institutions find difficulties in building a coherent local adaptation planning and design processes with international and national frameworks. In this context, this article proposes a methodology based on the available international frameworks to support the small communities with the aim to implement adaptation pilot projects within different sectors. In doing so, this paper tests a climate change adaptation cycle for pilot projects development in small municipalities; the first in Italy for small municipalities under 20.000 inhabitants. The proposed methodology could lead local adaptation initiatives in climate change risk assessment by supporting the research communities in developing a coherent vision for the local territories and to identify proper oriented measures to enhance demonstrative pilot projects and to increase the level of resilience in small municipalities, avoiding maladaptation.
Abstract Aim An innovative xenon–chlorine (excimer) pulsed laser catheter (ELCA X80) has been recently used for the treatment of complex coronary lesions, as calcified stenosis, chronic total ...occlusions and non-compliant plaques. Such complex lesions are difficult to adequately treat with balloon angioplasty and/or intracoronary stenting. The aim of this study was to examine the acute outcome of this approach on a cohort of patients with coronary lesions. Methods and Results Eighty patients with 100 lesions were enrolled through four centers, and excimer laser coronary angioplasty was performed on 96 lesions (96%). Safety and effectiveness data were compared between patients treated with standard laser therapy and those treated with increased laser therapy. Laser success was obtained in 90 lesions (93.7%), procedural success was reached in 88 lesions (91.7%), and clinical success in was obtained in 87 lesions (90.6%). There was no perforation, major side branch occlusion, spasm, no-reflow phenomenon, dissection nor acute vessel closure. Increased laser parameters were used successfully for 49 resistant lesions without complications. Conclusions This study suggests that laser-facilitated coronary angioplasty is a simple, safe and effective device for the management of complex coronary lesions. Furthermore, higher laser energy levels delivered by this catheter improved the device performance without increasing complications.
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