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

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

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

Mothers' accounts of their stillbirth experiences and of their subsequent relationships with their living infant:an interpretative phenomenological analysis

BACKGROUND: Due to contradictory findings regarding the effects of seeing and holding stillborn infants on women's worsening mental health symptoms, there is a lack of clear of guidance in stillbirth bereavement care. Although some current research examines this phenomenon we are still not certain of the meaning of such experiences to women and what effects there may be on her subsequent parenting. Thus the present study focuses on the meaning of the stillbirth experience to women and its influence on the subsequent pregnancy and subsequent parenting from the mothers' own experiences. METHODS: A purposive sample of six women who experienced a stillbirth during their first pregnancy and who then went on to give birth to a living child after a further pregnancy, took part in email interviews, providing rich and detailed experiential narratives about both the stillbirth itself, and their relationship with their living child. An Interpretive Phenomenological Analysis was carried out in order to focus on mothers making sense of such experiences. RESULTS: Analysis of written accounts led to the development of three overarching themes. In 'Broken Canopy', 'How This Happened' and 'Continuing Bonds', their accounts revealed an ongoing process where women accepted a new 'unsafe' view of the world, re-evaluated their view of self and others, and established relationships with both the deceased and the living infant. CONCLUSIONS: This study provided an insight into the stillbirth experience of mothers and its meaning to them with an existential focus. Typically the mother struggled with the contradictory process of accepting the existence of her deceased baby (this baby once lived) while being aware of the nonexistence (this baby). Meeting the dead baby was a crucial point at which the mother started processing her grief. The importance of individual differences in dealing with stressful situations was highlighted in terms of attachment strategies. Subsequent parenting experiences of mothers were very much influenced by their own previous experiences. Although some mothers managed to integrate this trauma into their life some remained very concerned and anxious about future and this anxiety then translated into their parenting experiences

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

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

Are we ready to track climate-driven shifts in marine species across international boundaries? - A global survey of scientific bottom trawl data

Marine biota are redistributing at a rapid pace in response to climate change and shifting seascapes. While changes in fish populations and community structure threaten the sustainability of fisheries, our capacity to adapt by tracking and projecting marine species remains a challenge due to data discontinuities in biological observations, lack of data availability, and mismatch between data and real species distributions. To assess the extent of this challenge, we review the global status and accessibility of ongoing scientific bottom trawl surveys. In total, we gathered metadata for 283,925 samples from 95 surveys conducted regularly from 2001 to 2019. We identified that 59% of the metadata collected are not publicly available, highlighting that the availability of data is the most important challenge to assess species redistributions under global climate change. Given that the primary purpose of surveys is to provide independent data to inform stock assessment of commercially important populations, we further highlight that single surveys do not cover the full range of the main commercial demersal fish species. An average of 18 surveys is needed to cover at least 50% of species ranges, demonstrating the importance of combining multiple surveys to evaluate species range shifts. We assess the potential for combining surveys to track transboundary species redistributions and show that differences in sampling schemes and inconsistency in sampling can be overcome with spatio-temporal modeling to follow species density redistributions. In light of our global assessment, we establish a framework for improving the management and conservation of transboundary and migrating marine demersal species. We provide directions to improve data availability and encourage countries to share survey data, to assess species vulnerabilities, and to support management adaptation in a time of climate-driven ocean changes.En prensa6,86