Pulse-Echo Quantitative US Biomarkers for Liver Steatosis: Toward Technical Standardization

Excessive liver fat (steatosis) is now the most common cause of chronic liver disease worldwide and is an independent risk factor for cirrhosis and associated complications. Accurate and clinically useful diagnosis, risk stratification, prognostication, and therapy monitoring require accurate and reliable biomarker measurement at acceptable cost. This article describes a joint effort by the American Institute of Ultrasound in Medicine (AIUM) and the RSNA Quantitative Imaging Biomarkers Alliance (QIBA) to develop standards for clinical and technical validation of quantitative biomarkers for liver steatosis. The AIUM Liver Fat Quantification Task Force provides clinical guidance, while the RSNA QIBA Pulse-Echo Quantitative Ultrasound Biomarker Committee develops methods to measure biomarkers and reduce biomarker variability. In this article, the authors present the clinical need for quantitative imaging biomarkers of liver steatosis, review the current state of various imaging modalities, and describe the technical state of the art for three key liver steatosis pulse-echo quantitative US biomarkers: attenuation coefficient, backscatter coefficient, and speed of sound. Lastly, a perspective on current challenges and recommendations for clinical translation for each biomarker is offered

Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study

Hemodialysis vascular access monitoring: Current concepts

Most arteriovenous grafts fail due to irreversible thrombosis, and most clotted grafts have an underlying stenotic lesion. These observations raise the plausible hypothesis that, early detection of graft stenosis with preemptive angioplasty will reduce the likelihood of graft thrombosis. A number of noninvasive methods can be used to detect hemodynamically significant graft stenosis with a high positive predictive value. These tests include clinical monitoring, as well as surveillance by static dialysis venous pressures, flow monitoring, or duplex ultrasound. However, these surveillance tests have a much lower positive predictive value for graft thrombosis in the absence of preemptive angioplasty. In other words, none of the currently available surveillance tests can reliably distinguish between stenosed grafts destined to clot, and those that will remain patent without intervention. As a consequence, any program of graft surveillance necessarily results in a substantial proportion of unnecessary angioplasties. Moreover, a substantial proportion of grafts thrombose despite a normal antecedent surveillance test. Numerous observational studies have found an impressive reduction of graft thrombosis after implementation of a stenosis surveillance program. In contrast, 5 of 6 randomized clinical trials failed to show a reduction of graft thrombosis in patients undergoing graft surveillance, as compared with those receiving only clinical monitoring. The lack of benefit of surveillance is largely attributable to the rapid recurrence of stenosis after angioplasty. Thus, routine surveillance for graft stenosis, with preemptive angioplasty, cannot be recommended for reduction of graft thrombosis. Future research should be directed at pharmacologic interventions to prevent graft stenosis

Increasing arteriovenous fistulas in hemodialysis patients: Problems and solutions

Increasing arteriovenous fistulas in hemodialysis patients: Problems and solutions. National guidelines promote increasing the prevalence of fistula use among hemodialysis patients. The prevalence of fistulas among hemodialysis patients reflects both national, regional, and local practice differences as well as patient-specific demographic and clinical factors. Increasing fistula prevalence requires increasing fistula placement, improving maturation of new fistulas, and enhancing long-term patency of mature fistulas for dialysis. Whether a patient receives a fistula depends on several factors: timing of referral for dialysis and vascular access, type of fistula placed, patient demographics, preference of the nephrologist, surgeon, and dialysis nurses, and vascular anatomy of the patient. Whether the placed fistula is useable for dialysis depends on additional factors, including adequacy of vessels, surgeon's experience, patient demographics, nursing skills, minimal acceptable dialysis blood flow, and attempts to revise immature fistulas. Whether a mature fistula achieves long-term patency depends on the ability to prevent and correct thrombosis. An optimal outcome is likely when there is (1) a multidisciplinary team approach to vascular access; (2) consensus about the goals among all interested parties (nephrologists, surgeons, radiologists, dialysis nurses, and patients); (3) early referral for placement of vascular access; (4) restriction of vascular access procedures to surgeons with demonstrable interest and experience; (5) routine, preoperative mapping of the patient's arteries and veins; (6) close, ongoing communication among the involved parties; and (7) prospective tracking of outcomes with continuous quality assessment. Implementing these measures is likely to increase the prevalence of fistulas in any given dialysis unit. However, differences among dialysis units are likely to persist because of differences in gender, race, and co-morbidity mix of the patient population