Lack of Association between Genetic Polymorphisms in Enzymes Associated with Folate Metabolism and Unexplained Reduced Sperm Counts

BACKGROUND: The metabolic pathway of folate is thought to influence DNA stability either by inducing single/double stranded breaks or by producing low levels of S-adenosyl-methionine leading to abnormal gene expression and chromosome segregation. Polymorphisms in the genes encoding enzymes in the folate metabolism pathway show distinct geographic and/or ethnic variations and in some cases have been linked to disease. Notably, the gene Methylenetetrahydrofolate reductase (MTHFR) in which the homozygous (TT) state of the polymorphism c.665C>T (p.A222V) is associated with reduced specific activity and increased thermolability of the enzyme causing mild hyperhomocysteinemia. Recently several studies have suggested that men carrying this polymorphism may be at increased risk to develop infertility. METHODOLOGY/PRINCIPAL FINDINGS: We have tested this hypothesis in a case/control study of ethnic French individuals. We examined the incidence of polymorphisms in the genes MTHFR (R68Q, A222V and E429A), Methionine synthase reductase MTRR; (I22M and S175L) and Cystathionine beta-synthase (CBS; G307S). The case population consisted of DNA samples from men with unexplained azoospermia (n = 70) or oligozoospermia (n = 182) and the control population consisted of normospermic and fertile men (n = 114). We found no evidence of an association between the incidence of any of these variants and reduced sperm counts. In addition haplotype analysis did not reveal differences between the case and control populations. CONCLUSIONS/SIGNIFICANCE: We could find no evidence for an association between reduced sperm counts and polymorphisms in enzymes involved in folate metabolism in the French population

Interferon-free therapy for genotype 1 hepatitis C in liver transplant recipients: Real-world experience from the hepatitis C therapeutic registry and research network.

Recurrent infection with the hepatitis C virus (HCV) after liver transplantation (LT) is associated with decreased graft and patient survival. Achieving sustained virological response (SVR) with antiviral therapy improves survival. Because interferon (IFN)-based therapy has limited efficacy and is poorly tolerated, there has been rapid transition to IFN-free direct-acting antiviral (DAA) regimens. This article describes the experience with DAAs in the treatment of posttransplant genotype (GT) 1 HCV from a consortium of community and academic centers (Hepatitis C Therapeutic Registry and Research Network [HCV-TARGET]). Twenty-one of the 54 centers contributing to the HCV-TARGET consortium participated in this study. Enrollment criteria included positive posttransplant HCV RNA before treatment, HCV GT 1, and documentation of use of a simeprevir (SMV)/sofosbuvir (SOF) containing DAA regimen. Safety and efficacy were assessed. SVR was defined as undetectable HCV RNA 64 days or later after cessation of treatment. A total of 162 patients enrolled in HCV-TARGET started treatment with SMV+SOF with or without ribavirin (RBV) following LT. The study population included 151 patients treated with these regimens for whom outcomes and safety data were available. The majority of the 151 patients were treated with SOF and SMV alone (n = 119; 79%) or with RBV (n = 32; 21%), The duration of therapy was 12 weeks for most patients, although 15 patients received 24 weeks of treatment. Of all patients receiving SOF/SMV with or without RBV, 133/151 (88%) achieved sustained virological response at 12 weeks after therapy and 11 relapsed (7%). One patient had virological breakthrough (n = 1), and 6 patients were lost to posttreatment follow-up. Serious adverse events occurred in 11.9%; 3 patients (all cirrhotic) died due to aspiration pneumonia, suicide, and multiorgan failure. One experienced LT rejection. IFN-free DAA treatment represents a major improvement over prior IFN-based therapy. Broader application of these and other emerging DAA regimens in the treatment of posttransplant hepatitis C is warranted

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events

Advancing Transplantation:New Questions, New Possibilities in Kidney and Liver Transplantation

Disclosure and contributions: This supplement collects a number of the sessions from the meeting 'Advancing Transplantation: New Questions, New Possibilities'. The meeting was sponsored by Astellas Pharma Europe Ltd; the agenda was developed by Astellas in collaboration with the meeting's scientific committee: J Wadström, BG Ericzon, WO Bechstein, D Serón and PF Halloran. The event was approved by the Federation of the Royal Colleges of Physicians of the United Kingdom for 12 category 1 (external) CPD credits. The scientific committee and faculty developed their own content for the meeting with editorial support from iS Health Group. Editorial support for the meeting was funded by Astellas Pharma Europe Ltd. Previously unpublished data that could not be included, due to existing embargo policies or to protect intellectual property, have been excluded from this report. The unpublished data in this report were included at the discretion of the authors as personal communications. Based on the presentations given at the meeting and under the direction of the authors, iS LifeScience provided editorial support throughout the development of this supplement. Editorial support was funded by Astellas Pharma Europe Ltd. A.L., in his role as the Guest Editor, reviewed this supplement and advised on the content throughout the development process. The authors had final authority over the editorial content and approved the final version of this supplement before submission. Astellas Pharma and associated companies developed, manufacture and supply tacrolimus (tacrolimus hard capsules (Prograf), tacrolimus prolonged-release hard capsules (Advagraf)). Prescribing information and adverse event reporting information can be found on pages S40-S41. J.W. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work. B-G.E reports nonfinancial support from Astellas, during the development of this supplement; honoraria and consultancy fees from Astellas, Pfizer and Novartis and clinical trial support from Novartis and Astellas, outside of the submitted work. P.H. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work shares in TSI, a university company with an interest in molecular diagnostics. W.B. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work. G.O. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work D.S. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work J.G. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work. A.L. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work. D.K. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work CM. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work. M.C. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work. A.J. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, Opsona Therapeutics, AstraZeneca, Bayer and Pfizer, outside the submitted work. L.G. reports personal fees from Astellas during the conduct of the study for acting as a conference speaker; personal fees from Astellas, personal fees from Novartis, personal fees from Pfizer, personal fees from Roche, outside the submitted work. B.F. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, grants from BMS, grants and consulting fees from Pharmalink, and lecturing fees from Sandoz, outside of the submitted work. J.O.G. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work. J.P. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work. J.O.L. reports nonfinancial support from Astellas, during the development this supplement; nonfinancial support and personal fees from Astellas, personal fees from Novartis, and grants from Fisher Scientific, outside of the submitted work. V.A. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work. P.T. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work. U.B. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support from and personal fees from Astellas, outside the submitted work. J.N. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, and personal fees from Novartis, outside of the submitted work; employment as a consultant physician at Queen Elizabeth Hospital, Birmingham. A.S.-G. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work. E.G. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support from Astellas, and personal fees from Astellas, Pfizer and Novartis, outside the submitted work. M.M. reports nonfinancial support from Astellas, during the development of this supplement; non-financial support and personal fees from Astellas, outside of the submitted work. M.G. reports nonfinancial support from Astellas during the development of this supplement; nonfinancial support from Astellas and personal fees from Astellas, outside the submitted wor

Banff 2022 liver group meeting report: monitoring long term allograft health.

The Banff Working Group on Liver Allograft Pathology met in September 2022. Participantsincluded hepatologists, surgeons, pathologists, immunologists and histocompatibility specialists.Presentations and discussions focused on the evaluation of long-term allograft health, including noninvasive and tissue monitoring, immunosuppression optimisation and long-term structural changes.Potential revision of the rejection classification scheme to better accommodate and communicate lateT cell-mediated rejection patterns and related structural changes, such as nodular regenerativehyperplasia, were discussed. Improved stratification of long-term maintenance immunosuppression tomatch the heterogeneity of patient settings will be central to improving long-term patient survival.Such personalised therapeutics are in turn contingent on better understanding and monitoring ofallograft status within a rational decision-making approach, likely to be facilitated in implementationwith emerging decision support tools. Proposed revisions to rejection classification emerging fromthe meeting include incorporation of interface hepatitis and fibrosis staging. These will be opened toonline testing, modified accordingly and subject to consensus discussion leading up to the next Banffconference

Combination of novel and public RNA-seq datasets to generate an mRNA expression atlas for the domestic chicken

Background: The domestic chicken (Gallus gallus) is widely used as a model in developmental biology and is also an important livestock species. We describe a novel approach to data integration to generate an mRNA expression atlas for the chicken spanning major tissue types and developmental stages, using a diverse range of publicly-archived RNA-seq datasets and new data derived from immune cells and tissues. Results: Randomly down-sampling RNA-seq datasets to a common depth and quantifying expression against a reference transcriptome using the mRNA quantitation tool Kallisto ensured that disparate datasets explored comparable transcriptomic space. The network analysis tool Graphia was used to extract clusters of co-expressed genes from the resulting expression atlas, many of which were tissue or cell-type restricted, contained transcription factors that have previously been implicated in their regulation, or were otherwise associated with biological processes, such as the cell cycle. The atlas provides a resource for the functional annotation of genes that currently have only a locus ID. We cross-referenced the RNA-seq atlas to a publicly available embryonic Cap Analysis of Gene Expression (CAGE) dataset to infer the developmental time course of organ systems, and to identify a signature of the expansion of tissue macrophage populations during development. Conclusion: Expression profiles obtained from public RNA-seq datasets - despite being generated by different laboratories using different methodologies - can be made comparable to each other. This meta-analytic approach to RNA-seq can be extended with new datasets from novel tissues, and is applicable to any species

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP