Biomarkers differentiate drug-induced liver injury from other liver injury: PONDER study

Background and Aim: Drug-induced liver injury (DILI) is a known complication of volatile anesthetic (VA) agents, and, despite being rare, DILI can be serious. One mechanism of VA-DILI occurs via interleukin 4 (IL-4)driven upregulation of cytochrome P450-2E1, leading to the formation of drug metabolites (haptens) that trigger IL-4-driven antigen-specific T cells and autoantibodies. Our group has developed biomarkers for liver injury and have examined this in patients before and after VA exposure. The aim of this prospective study was to determine the early markers of VA-DILI. Methods: We prospectively followed patients having a VA general anesthetic (sevoflurane and/or desflurane) and compared them with those who received regional or total intravenous anesthesia. Exclusion criteria were known liver disease or any episode of significant hypotension. Baseline data on patient demographics and comorbidities were collected, and blood was analyzed for liver biochemistry, macrophage activation markers (CD206, CD163), and IgG1 and IgG4 antibodies to JHDN5 (the CYP2E1 epitope) and trifluoroacetyl (TFA), the VA drug hapten. Follow-up blood samples were taken 48 h postoperatively and compared with baseline results. DILI was defined as an alanine aminotransferase (ALT) level greater than two times the upper limit of normal (ULN) and post-review agreement by an expert panel, taking into account the pattern of liver function test result derangement and intraoperative events. Results: Of 229 patients recruited, 16 developed an ALT level > 2 × ULN. Twelve were considered likely to have VA-DILI, including four with an ALT rise >3 × ULN. There was a trend to associate VA-DILI with obesity (RR, 2.98; P = 0.063); however, the association with dyslipidemia (RR, 1.47; P = 0.72), male sex (RR, 1.18; P = 0.76), history of atopy (RR, 1.16; P = 0.79), and heavy ethanol consumption (RR, 1.09; P = 0.89) was not statistically significant. Prior VA exposure was not a risk factor (RR, 0.89; P = 0.83). There was a rise in CD206 and decline in CD163 from baseline in all patients. However, in the patients with VA-DILI, the levels were significantly different from all other groups. TFA IgG1 and IgG4 antibodies were elevated in the VA-DILI group when compared with controls. Conclusion: Recognizing that our results may be skewed by our cohort, this work suggests the known immunological pathway mediated by IL-4 in response to an injury: rise in CD206 to stimulate an inflammatory response, and decrease in CD163 to modulate the response. The increase in TFA IgG1 and IgG4 antibodies in the VA-DILI group is consistent with metabolism and the heightened immune response in those who develop DILI. At this early juncture, JHDN5 IgG4 autoantibodies were not detected. Ongoing work is looking at other DILI, and how these markers can be used in DILI

Copy Number Variation Affecting the Photoperiod-B1 and Vernalization-A1 Genes Is Associated with Altered Flowering Time in Wheat (Triticum aestivum)

The timing of flowering during the year is an important adaptive character affecting reproductive success in plants and is critical to crop yield. Flowering time has been extensively manipulated in crops such as wheat (Triticum aestivum L.) during domestication, and this enables them to grow productively in a wide range of environments. Several major genes controlling flowering time have been identified in wheat with mutant alleles having sequence changes such as insertions, deletions or point mutations. We investigated genetic variants in commercial varieties of wheat that regulate flowering by altering photoperiod response (Ppd-B1 alleles) or vernalization requirement (Vrn-A1 alleles) and for which no candidate mutation was found within the gene sequence. Genetic and genomic approaches showed that in both cases alleles conferring altered flowering time had an increased copy number of the gene and altered gene expression. Alleles with an increased copy number of Ppd-B1 confer an early flowering day neutral phenotype and have arisen independently at least twice. Plants with an increased copy number of Vrn-A1 have an increased requirement for vernalization so that longer periods of cold are required to potentiate flowering. The results suggest that copy number variation (CNV) plays a significant role in wheat adaptation

Arthroscopic observation was useful to detect loosening of the femoral component of unicompartmental knee arthroplasty in a recurrent hemoarthrosis

A case of recurrent hemarthrosis of the knee after a mobile-bearing unicompartmental knee arthroplasty (UKA; Oxford UKA) is described. A 58-year-old man met with a road traffic accident 10 months after UKA. He developed anteromedial pain and hemarthrosis of the knee joint 1 month after the accident, which required multiple aspirations. Physical examination showed no instability. Plain radiograph revealed no signs of loosening. All laboratory data, including bleeding and coagulation times, were within normal limits. Diagnostic arthroscopy demonstrated loosening of the femoral component. Any intraarticular pathology other than nonspecific synovitis was ruled out. The loose femoral component and polyethylene meniscal bearing were revised. Since then, hemarthrosis has not recurred

Flavopiridol Pharmacogenetics: Clinical and Functional Evidence for the Role of SLCO1B1/OATP1B1 in Flavopiridol Disposition

Flavopiridol is a cyclin-dependent kinase inhibitor in phase II clinical development for treatment of various forms of cancer. When administered with a pharmacokinetically (PK)-directed dosing schedule, flavopiridol exhibited striking activity in patients with refractory chronic lymphocytic leukemia. This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy.Thirty-five patients who received single-agent flavopiridol via the PK-directed schedule were genotyped for 189 polymorphisms in genes encoding 56 drug metabolizing enzymes and transporters. Genotypes were evaluated in univariate and multivariate analyses as covariates in a population PK model. Transport of flavopiridol and its glucuronide metabolite was evaluated in uptake assays in HEK-293 and MDCK-II cells transiently transfected with SLCO1B1. Polymorphisms in ABCC2, ABCG2, UGT1A1, UGT1A9, and SLCO1B1 were found to significantly correlate with flavopiridol PK in univariate analysis. Transport assay results indicated both flavopiridol and flavopiridol-glucuronide are substrates of the SLCO1B1/OATP1B1 transporter. Covariates incorporated into the final population PK model included bilirubin, SLCO1B1 rs11045819 and ABCC2 rs8187710. Associations were also observed between genotype and response. To validate these findings, a second set of data with 51 patients was evaluated, and overall trends for associations between PK and PGx were found to be consistent.Polymorphisms in transport genes were found to be associated with flavopiridol disposition and outcomes. Observed clinical associations with SLCO1B1 were functionally validated indicating for the first time its relevance as a transporter of flavopiridol and its glucuronide metabolite. A second 51-patient dataset indicated similar trends between genotype in the SLCO1B1 and other candidate genes, thus providing support for these findings. Further study in larger patient populations will be necessary to fully characterize and validate the clinical impact of polymorphisms in SLCO1B1 and other transporter and metabolizing enzyme genes on outcomes from flavopiridol therapy

The U.S. water data gap: A survey of state-level water data platforms to inform the development of a national water portal

Water data play a crucial role in the development and assessment of sustainable water management strategies. Water resource assessments are needed for the planning, management, and the evaluation of current practices. They require environmental, climatic, hydrologic, hydrogeologic, industrial, agricultural, energy, and socioeconomic data to assess and accurately project the supply of and demand for water services. Given this context, we provide a review of the current state of publicly available water data in the United States. While considerable progress has been made in data science and model development in recent years, data limitations continue to hamper analytics. A brief overview of the water data sets available at the federal level is used to highlight the gaps in readily accessible water data in the United States. Then, we present a systematic review of 275 websites that provide water information collected at the state level. Data platforms are evaluated based on content (ground and surface water, water quality, and water use information) along with the analytical and exploratory tools that are offered. Wev discuss the degree to which existing state-level data sets could enrich the data available from federal sources and review some recent technological developments and initiatives that may modernize water data. We argue that a national water data portal, more comprehensive than the U.S. Energy Information Administration, addressing the significant gaps and centralizing water data is critical. It would serve to quantify the risks emerging from growing water stress and aging infrastructure and to better inform water management and investment decisions

A haplotype map of allohexaploid wheat reveals distinct patterns of selection on homoeologous genomes

BACKGROUND: Bread wheat is an allopolyploid species with a large, highly repetitive genome. To investigate the impact of selection on variants distributed among homoeologous wheat genomes and to build a foundation for understanding genotype-phenotype relationships, we performed population-scale re-sequencing of a diverse panel of wheat lines. RESULTS: A sample of 62 diverse lines was re-sequenced using the whole exome capture and genotyping-by-sequencing approaches. We describe the allele frequency, functional significance, and chromosomal distribution of 1.57 million single nucleotide polymorphisms and 161,719 small indels. Our results suggest that duplicated homoeologous genes are under purifying selection. We find contrasting patterns of variation and inter-variant associations among wheat genomes; this, in addition to demographic factors, could be explained by differences in the effect of directional selection on duplicated homoeologs. Only a small fraction of the homoeologous regions harboring selected variants overlapped among the wheat genomes in any given wheat line. These selected regions are enriched for loci associated with agronomic traits detected in genome-wide association studies. CONCLUSIONS: Evidence suggests that directional selection in allopolyploids rarely acted on multiple parallel advantageous mutations across homoeologous regions, likely indicating that a fitness benefit could be obtained by a mutation at any one of the homoeologs. Additional advantageous variants in other homoelogs probably either contributed little benefit, or were unavailable in populations subjected to directional selection. We hypothesize that allopolyploidy may have increased the likelihood of beneficial allele recovery by broadening the set of possible selection targets