The genome of the colonial hydroid Hydractinia reveals that their stem cells use a toolkit of evolutionarily shared genes with all animals.

Hydractinia is a colonial marine hydroid that shows remarkable biological properties, including the capacity to regenerate its entire body throughout its lifetime, a process made possible by its adult migratory stem cells, known as i-cells. Here, we provide an in-depth characterization of the genomic structure and gene content of two Hydractinia species, Hydractinia symbiolongicarpus and Hydractinia echinata, placing them in a comparative evolutionary framework with other cnidarian genomes. We also generated and annotated a single-cell transcriptomic atlas for adult male H. symbiolongicarpus and identified cell-type markers for all major cell types, including key i-cell markers. Orthology analyses based on the markers revealed that Hydractinia's i-cells are highly enriched in genes that are widely shared amongst animals, a striking finding given that Hydractinia has a higher proportion of phylum-specific genes than any of the other 41 animals in our orthology analysis. These results indicate that Hydractinia's stem cells and early progenitor cells may use a toolkit shared with all animals, making it a promising model organism for future exploration of stem cell biology and regenerative medicine. The genomic and transcriptomic resources for Hydractinia presented here will enable further studies of their regenerative capacity, colonial morphology, and ability to distinguish self from nonself.

Giant lungfish genome elucidates the conquest of land by vertebrates.

Lungfishes belong to lobe-fined fish (Sarcopterygii) that, in the Devonian period, 'conquered' the land and ultimately gave rise to all land vertebrates, including humans1-3. Here we determine the chromosome-quality genome of the Australian lungfish (Neoceratodus forsteri), which is known to have the largest genome of any animal. The vast size of this genome, which is about 14× larger than that of humans, is attributable mostly to huge intergenic regions and introns with high repeat content (around 90%), the components of which resemble those of tetrapods (comprising mainly long interspersed nuclear elements) more than they do those of ray-finned fish. The lungfish genome continues to expand independently (its transposable elements are still active), through mechanisms different to those of the enormous genomes of salamanders. The 17 fully assembled lungfish macrochromosomes maintain synteny to other vertebrate chromosomes, and all microchromosomes maintain conserved ancient homology with the ancestral vertebrate karyotype. Our phylogenomic analyses confirm previous reports that lungfish occupy a key evolutionary position as the closest living relatives to tetrapods4,5, underscoring the importance of lungfish for understanding innovations associated with terrestrialization. Lungfish preadaptations to living on land include the gain of limb-like expression in developmental genes such as hoxc13 and sall1 in their lobed fins. Increased rates of evolution and the duplication of genes associated with obligate air-breathing, such as lung surfactants and the expansion of odorant receptor gene families (which encode proteins involved in detecting airborne odours), contribute to the tetrapod-like biology of lungfishes. These findings advance our understanding of this major transition during vertebrate evolution.

Using cultural historical activity theory to reflect on the sociocultural complexities in OSCE examiners' judgements.

Examiners' judgements play a critical role in competency-based assessments such as objective structured clinical examinations (OSCEs). The standardised nature of OSCEs and their alignment with regulatory accountability assure their wide use as high-stakes assessment in medical education. Research into examiner behaviours has predominantly explored the desirable psychometric characteristics of OSCEs, or investigated examiners' judgements from a cognitive rather than a sociocultural perspective. This study applies cultural historical activity theory (CHAT) to address this gap in exploring examiners' judgements in a high-stakes OSCE. Based on the idea that OSCE examiners' judgements are socially constructed and mediated by their clinical roles, the objective was to explore the sociocultural factors that influenced examiners' judgements of student competence and use the findings to inform examiner training to enhance assessment practice. Seventeen semi-structured interviews were conducted with examiners who assessed medical student competence in progressing to the next stage of training in a large-scale OSCE at one Australian university. The initial thematic analysis provided a basis for applying CHAT iteratively to explore the sociocultural factors and, specifically, the contradictions created by interactions between different elements such as examiners and rules, thus highlighting the factors influencing examiners' judgements. The findings indicated four key factors that influenced examiners' judgements: examiners' contrasting beliefs about the purpose of the OSCE; their varying perceptions of the marking criteria; divergent expectations of student competence; and idiosyncratic judgement practices. These factors were interrelated with the activity systems of the medical school's assessment practices and the examiners' clinical work contexts. Contradictions were identified through the guiding principles of multi-voicedness and historicity. The exploration of the sociocultural factors that may influence the consistency of examiners' judgements was facilitated by applying CHAT as an analytical framework. Reflecting upon these factors at organisational and system levels generated insights for creating fit-for-purpose examiner training to enhance assessment practice.

Evaluation of a co-designed Parkinson's awareness audio podcast for undergraduate nursing students in Northern Ireland.

BACKGROUND: Parkinson's Disease (PD) is a common neurological condition that often causes stiffness, tremor and slow movement. People living with PD are likely to encounter nursing students throughout their journey from pre-diagnosis to death. Despite this, there is a paucity of evidence about current practice in PD education amongst nursing students. The present study provides an evaluation of a co-designed Parkinson's Awareness audio podcast amongst nursing students in Northern Ireland. METHODS: Following co-design of an audio podcast about PD, a mixed methods evaluation was carried out. 332 student nurses completed pre-/post-test questionnaires about their knowledge and perceptions of PD before and after listening to the audio podcast. Further to this, 35 student nurses participated in focus-group interviews six months following listening to explore how the podcast influenced practice. RESULTS: Student nurses posted a mean score of 52% before listening to the audio podcast. This mean increased to 80% post-test. These findings were statistically significant (p < 0.001), demonstrating significant increases in PD awareness after listening. Findings from the focus groups suggested that the audio podcast improved empathy and practice towards people with PD. The findings also suggested that students perceived audio podcasts to be a good way to learn about PD. CONCLUSION: Provision of a co-designed audio podcast about PD has the potential to improve student nurse knowledge and practice related to PD as evidenced in this study.

Expansion of a single transposable element family is associated with genome-size increase and radiation in the genus Hydra.

Transposable elements are one of the major contributors to genome-size differences in metazoans. Despite this, relatively little is known about the evolutionary patterns of element expansions and the element families involved. Here we report a broad genomic sampling within the genus Hydra, a freshwater cnidarian at the focal point of diverse research in regeneration, symbiosis, biogeography, and aging. We find that the genome of Hydra is the result of an expansion event involving long interspersed nuclear elements and in particular a single family of the chicken repeat 1 (CR1) class. This expansion is unique to a subgroup of the genus Hydra, the brown hydras, and is absent in the green hydra, which has a repeat landscape similar to that of other cnidarians. These features of the genome make Hydra attractive for studies of transposon-driven genome expansions and speciation.

Engaging clinical examiners with structured feedback to enhance assessment practices.

INTRODUCTION: Examiners' professional judgements of student performance are pivotal to making high-stakes decisions to ensure graduating medical students are competent to practise. Clinicians play a key role in assessment in medical education. They are qualified in their clinical area but may require support to further develop their understanding of assessment practices. However, there are limited studies on providing examiners with structured feedback on their assessment practices for professional development purposes. METHODS: This study adopts an interpretive paradigm to develop an understanding of clinical examiners' interpretations of receiving structured feedback and its impacts on enhancing their assessment literacy and practice. Data were collected from 29 interviews with clinical examiners who assessed the final-year medical objective structured clinical examinations (OSCEs) at one university. RESULTS: Inductive thematic analysis of these data revealed that the examiners considered the feedback to be useful with practical functions in facilitating communication, comparisons and self-reflection. However, the examiners' level of confidence in the appropriateness of their assessment practices and difficulties in interpreting feedback could be barriers to adopting better practices. CONCLUSION: Feedback for examiners needs to be practical, targeted, and relevant to support them making accountable and defensible judgements of student performance.

Opioids in patients with COPD and refractory dyspnea: literature review and design of a multicenter double blind study of low dosed morphine and fentanyl (MoreFoRCOPD).

BACKGROUND: Refractory dyspnea or breathlessness is a common symptom in patients with advanced chronic obstructive pulmonary disease (COPD), with a high negative impact on quality of life (QoL). Low dosed opioids have been investigated for refractory dyspnea in COPD and other life-limiting conditions, and some positive effects were demonstrated. However, upon first assessment of the literature, the quality of evidence in COPD seemed low or inconclusive, and focused mainly on morphine which may have more side effects than other opioids such as fentanyl. For the current publication we performed a systematic literature search. We searched for placebo-controlled randomized clinical trials investigating opioids for refractory dyspnea caused by COPD. We included trials reporting on dyspnea, health status and/or QoL. Three of fifteen trials demonstrated a significant positive effect of opioids on dyspnea. Only one of four trials reporting on QoL or health status, demonstrated a significant positive effect. Two-thirds of included trials investigated morphine. We found no placebo-controlled RCT on transdermal fentanyl. Subsequently, we hypothesized that both fentanyl and morphine provide a greater reduction of dyspnea than placebo, and that fentanyl has less side effects than morphine. METHODS: We describe the design of a robust, multi-center, double blind, double-dummy, cross-over, randomized, placebo-controlled clinical trial with three study arms investigating transdermal fentanyl 12 mcg/h and morphine sustained-release 10 mg b.i.d. The primary endpoint is change in daily mean dyspnea sensation measured on a numeric rating scale. Secondary endpoints are change in daily worst dyspnea, QoL, anxiety, sleep quality, hypercapnia, side effects, patient preference, and continued opioid use. Sixty patients with severe stable COPD and refractory dyspnea (FEV1 < 50%, mMRC ≥ 3, on optimal standard therapy) will be included. DISCUSSION: Evidence for opioids for refractory dyspnea in COPD is not as robust as usually appreciated. We designed a study comparing both the more commonly used opioid morphine, and transdermal fentanyl to placebo. The cross-over design will help to get a better impression of patient preferences. We believe our study design to investigate both sustained-release morphine and transdermal fentanyl for refractory dyspnea will provide valuable information for better treatment of refractory dyspnea in COPD. Trial registration NCT03834363 (ClinicalTrials.gov), registred at 7 Feb 2019, https://clinicaltrials.gov/ct2/show/NCT03834363 .

RepeatCraft: a meta-pipeline for repetitive element de-fragmentation and annotation.

SUMMARY: Repetitive elements comprise large proportion of many genomes. They have impact on both genome evolution and regulation. Their classification and the study of evolutionary history is a major emerging field. Various software exist to-date to classify and map repeats across genomes. The major unresolved drawback, however, is the fragmented nature of many identified repeat loci. This ultimately makes the classification of novel repeats and their evolutionary analyses difficult. To improve on this, we developed a pipeline (RepeatCraft) that integrates results from several repeat element classification tools based on both sequence similarity and structural features. The pipeline de-fragments closely spaced repeat loci in the genomes, reconstructing longer copies, thus allowing for a better annotation and sequence comparisons. The pipeline also includes a user interface that can run in a web browser allowing for an easy access and exploration of the repeat data. AVAILABILITY AND IMPLEMENTATION: RepeatCraft is implemented in Python and the web application is implemented in R. Download and documentation is freely available at https://github.com/niccw/repeatCraftp. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Effect of mid-follicular phase recombinant LH versus urinary HCG supplementation in poor ovarian responders undergoing IVF - a prospective double-blinded randomized study.

Luteinizing hormone (LH) is crucial for the development of follicular growth and oocyte maturation, especially in the management of poor ovarian responders (PORs). This study presents the results of a prospective double-blinded randomized study to compare the effect of mid-follicular phase recombinant LH (rLH) supplementation with urinary human chorionic gonadotrophin (uHCG) supplementation when using a fixed gonadotrophin-releasing hormone (GnRH) antagonist protocol in IVF cycles. A total of 49 women with poor ovarian response (POR) according to the Bologna criteria were recruited. This study showed no statistically significant difference in cycle cancellation rates, numbers of oocytes retrieved per cycle initiated, fertilization rates, the numbers of embryos obtained per cycle initiated, implantation, clinical pregnancy and live birth rates, although the live birth rate per cycle initiated in the uHCG group (29.2%) was 3.6 times that of the rLH group (8.0%). Further studies are required to verify if uHCG supplementation produces better clinical outcomes compared with rLH in women with POR.

"On the same page"? The effect of GP examiner feedback on differences in rating severity in clinical assessments: a pre/post intervention study.

BACKGROUND: Robust and defensible clinical assessments attempt to minimise differences in student grades which are due to differences in examiner severity (stringency and leniency). Unfortunately there is little evidence to date that examiner training and feedback interventions are effective; "physician raters" have indeed been deemed "impervious to feedback". Our aim was to investigate the effectiveness of a general practitioner examiner feedback intervention, and explore examiner attitudes to this. METHODS: Sixteen examiners were provided with a written summary of all examiner ratings in medical student clinical case examinations over the preceding 18 months, enabling them to identify their own rating data and compare it with other examiners. Examiner ratings and examiner severity self-estimates were analysed pre and post intervention, using non-parametric bootstrapping, multivariable linear regression, intra-class correlation and Spearman's correlation analyses. Examiners completed a survey exploring their perceptions of the usefulness and acceptability of the intervention, including what (if anything) examiners planned to do differently as a result of the feedback. RESULTS: Examiner severity self-estimates were relatively poorly correlated with measured severity on the two clinical case examination types pre-intervention (0.29 and 0.67) and were less accurate post-intervention. No significant effect of the intervention was identified, when differences in case difficulty were controlled for, although there were fewer outlier examiners post-intervention. Drift in examiner severity over time prior to the intervention was observed. Participants rated the intervention as interesting and useful, and survey comments indicated that fairness, reassurance, and understanding examiner colleagues are important to examiners. CONCLUSIONS: Despite our participants being receptive to our feedback and wanting to be "on the same page", we did not demonstrate effective use of the feedback to change their rating behaviours. Calibration of severity appears to be difficult for examiners, and further research into better ways of providing more effective feedback is indicated.

Inferior Alveolar Nerve Injury in Trauma-Induced Mandible Fractures.

PURPOSE: This prospective observational cohort study sought to determine the prevalence of inferior alveolar nerve (IAN) injury after mandibular fractures before and after treatment and to elucidate factors associated with the incidence of post-treatment IAN injury and time to normalization of sensation. MATERIALS AND METHODS: Consenting patients with mandibular fractures (excluding dentoalveolar, pathologic, previous fractures, or mandibular surgery) were prospectively evaluated for subjective neurosensory disturbance (NSD) and underwent neurosensory testing before treatment and then 1 week, 1.5, 3, 6, and 12 months after treatment. RESULTS: Eighty patients (men, 83.8%; mean age, 30.0 yr; standard deviation, 12.6 yr) with 123 mandibular sides (43 bilateral) were studied. Injury etiology included assault (33.8%), falls (31.3%), motor vehicle accidents (25.0%), and sports injuries (6.3%). Half the fractures (49.6%) involved the IAN-bearing posterior mandible; all condylar fractures (13.0%) had no NSD. Treatment included open reduction and internal fixation (ORIF; 74.8%), closed reduction and fixation (22.0%), or no treatment (3.3%). Overall prevalence of IAN injury was 33.7% (95% confidence interval [CI], 24.8-42.6) before treatment and 53.8% (95% CI, 46.0-61.6) after treatment. In the IAN-bearing mandible, the prevalence was 56.2% (95% CI, 43.2-69.2) before treatment and 72.9% (95% CI, 63.0-82.7) after treatment. In contrast, this prevalence in the non-IAN-bearing mandible was 12.6% (95% CI, 4.1-21.1) before treatment and 31.6% (95% CI, 20.0-43.3) after treatment. Factors associated with the development of post-treatment IAN injury included fracture site and gap distance (a 1-mm increase was associated with a 27% increase in odds of post-treatment sensory alteration). Time to normalization after treatment was associated with type of treatment (ORIF inhibited normalization) and fracture site (IAN-bearing sites took longer to normalize). CONCLUSION: IAN injury was 4 times more likely in IAN-bearing posterior mandibular fractures (56.2%) than in non-IAN-bearing anterior mandibular fractures (12.6%). After treatment, IAN injury prevalence (in 12 months) was higher (72.9% in posterior mandible, 31.6% in anterior mandible).

The genome of the colonial hydroid Hydractinia reveals their stem cells utilize a toolkit of evolutionarily shared genes with all animals.

Hydractinia is a colonial marine hydroid that exhibits remarkable biological properties, including the capacity to regenerate its entire body throughout its lifetime, a process made possible by its adult migratory stem cells, known as i-cells. Here, we provide an in-depth characterization of the genomic structure and gene content of two Hydractinia species, H. symbiolongicarpus and H. echinata, placing them in a comparative evolutionary framework with other cnidarian genomes. We also generated and annotated a single-cell transcriptomic atlas for adult male H. symbiolongicarpus and identified cell type markers for all major cell types, including key i-cell markers. Orthology analyses based on the markers revealed that Hydractinia's i-cells are highly enriched in genes that are widely shared amongst animals, a striking finding given that Hydractinia has a higher proportion of phylum-specific genes than any of the other 41 animals in our orthology analysis. These results indicate that Hydractinia's stem cells and early progenitor cells may use a toolkit shared with all animals, making it a promising model organism for future exploration of stem cell biology and regenerative medicine. The genomic and transcriptomic resources for Hydractinia presented here will enable further studies of their regenerative capacity, colonial morphology, and ability to distinguish self from non-self.

Repeat Age Decomposition Informs an Ancient Set of Repeats Associated With Coleoid Cephalopod Divergence.

In comparison with other molluscs and bilaterians, the genomes of coleoid cephalopods (squid, cuttlefish, and octopus) sequenced so far show remarkably different genomic organization that presumably marked the early evolution of this taxon. The main driver behind this genomic rearrangement remains unclear. About half of the genome content in coleoids is known to consist of repeat elements; since selfish DNA is one of the powerful drivers of genome evolution, its pervasiveness could be intertwined with the emergence of cephalopod-specific genomic signatures and could have played an important role in the reorganization of the cephalopod genome architecture. However, due to abundant species-specific repeat expansions, it has not been possible so far to identify the ancient shared set of repeats associated with coleoid divergence. By means of an extensive repeat element re-evaluation and annotation combined with network sequence divergence approaches, we are able to identify and characterize the ancient repeat complement shared by at least four coleoid cephalopod species. Surprisingly, instead of the most abundant elements present in extant genomes, lower-copy-number DNA and retroelements were most associated with ancient coleoid radiation. Furthermore, evolutionary analysis of some of the most abundant families shared in Octopus bimaculoides and Euprymna scolopes disclosed within-family patterns of large species-specific expansions while also identifying a smaller shared expansion in the coleoid ancestor. Our study thus reveals the apomorphic nature of retroelement expansion in octopus and a conserved complement composed of several DNA element types and fewer LINE families.

Health care students experience of using digital technology in patient care: A scoping review of the literature.

OBJECTIVES: To explore how undergraduate health care students use digital technology to deliver patient care during their clinical placements. DESIGN: A scoping review of primary research was conducted using the extended PRISMA guidelines. DATA SOURCES: A subject specialist librarian assisted in searching for the academic literature in four electronic databases: CINAHL, PubMed, Scopus and ERIC. REVIEW METHODS: Four reviewers, working in pairs, independently reviewed a total of 332 potentially relevant articles according to set inclusion and exclusion criteria. Then, all included papers underwent an independent quality review by two reviewers. RESULTS: Seven studies involving medical or nursing/midwifery students were included in the review. Three studies evaluated the use of mobile learning devices in patient care with four studies evaluating the use of digital systems in practice. Due to the heterogeneity of studies, which used differing digital systems and instruments, the researchers decided the most suitable method of analysis was a narrative review. The results are explained using four key themes: student learning needs when using technology in practice; access to technology in placements; perceptions of using technology in placements; and impact of technology on patient care. CONCLUSION: The use of digital systems in clinical settings creates challenges and benefits to student learning in delivering patient care. When students are prepared and facilitated to use digital systems, a sense of confidence and belonging to the team is fostered. Lack of availability and access to these systems, however, may impede students' ability to be involved in all aspects of patient care. Limitations of the current review included the relatively low quality of the educational research being conducted in this field of research. Further quality research is needed to explore how students in the health care professions are supported in digital environments and how higher education institutions are adapting their curricula to meet the digital learning needs of health care students.

Off to a good start after a cancer diagnosis: implementation of a time out consultation in primary care before cancer treatment decision.

PURPOSE: Supportive care for cancer patients may benefit from improving treatment decisions and optimal use of the family physicians' and specialists' strengths. To improve shared decision-making (SDM) and facilitate continuity of primary care during treatment, a cancer care path including a "time out consultation" (TOC) in primary care before treatment decision, was implemented. This study assesses the uptake of a TOC and the added value for SDM. METHODS: For patients with metastatic lung or gastro-intestinal cancer, a TOC was introduced in their care path in a southern region of The Netherlands, from April until October 2016. Uptake of a TOC was measured to reflect on facilitation of continuity of primary care. The added value for SDM and overall experiences were evaluated with questionnaires and semi-structured interviews among patients, family physicians, and specialists. RESULTS: Of the 40 patients who were offered a TOC, 31 (78%) had a TOC. Almost all patients, family physicians, and specialists expressed that they experienced added value for SDM. This includes a stimulating effect on reflection on choice (expressed by 83% of patients) and improved preparation for treatment decision (75% of patients). Overall added value of a TOC for SDM, only evaluated among family physicians and specialists, was experienced by 71% and 86% of these physicians, respectively. CONCLUSION AND IMPLICATIONS FOR CANCER SURVIVORS: The first experiences with a TOC in primary care before cancer treatment decision suggest that it may help to keep the GP "in the loop" after a cancer diagnosis and that it may contribute to the SDM process, according to patients, family physicians, and specialists.

Online examiner calibration across specialties.

BACKGROUND: Integrating undergraduate medical curricula horizontally across clinical medical specialties may be a more patient-centred and learner-centred approach than rotating students through specialty-specific teaching and assessment, but requires some interspecialty calibration of examiner judgements. Our aim was to evaluate the acceptability and feasibility of an online pilot of interdisciplinary examiner calibration. Fair clinical assessment is important to both medical students and clinical teachers METHODS: Clinical teachers were invited to rate video-recorded student objective structured clinical examination (OSCE) performances and join subsequent online discussions using the university's learning management system. Post-project survey free-text and Likert-scale participant responses were analysed to evaluate the acceptability of the pilot and to identify recommendations for improvement. RESULTS: Although 68 clinicians were recruited to participate, and there were 1599 hits on recordings and discussion threads, only 25 clinical teachers rated at least one student performance, and 18 posted at least one comment. Participants, including rural doctors, appeared to value the opportunity for interdisciplinary rating calibration and discussion. Although the asynchronous online format had advantages, especially for rural doctors, participants reported considerable IT challenges. DISCUSSION: Our findings suggest that fair clinical assessment is important to both medical students and clinical teachers. Interspecialty discussions about assessment may have the potential to enrich intraspecialty perspectives, enhance interspecialty engagement and collaboration, and improve the quality of clinical teacher assessment. Better alignment of university and hospital systems, a face to face component and other modifications may have enhanced clinician engagement with this project. Findings suggest that specialty assessment cultures and content expertise may not be barriers to pursuing more integrated approaches to assessment.

Effects of folic acid and zinc sulfate on male factor subfertility: a double-blind, randomized, placebo-controlled trial.

OBJECTIVE: To study the effects of folic acid and zinc sulfate treatment on semen variables in fertile and subfertile men. DESIGN: Double-blind, placebo-controlled interventional study. SETTING: Two outpatient fertility clinics and nine midwifery practices in The Netherlands. PARTICIPANT(S): One hundred eight fertile and 103 subfertile men. INTERVENTION(S): Both groups were randomly assigned to receive one of four treatments for 26 weeks: folic acid and placebo, zinc sulfate and placebo, zinc sulfate and folic acid, and two placebos. Folic acid was given at a daily dose of 5 mg, and zinc sulfate was given at a daily dose of 66 mg. MAIN OUTCOME MEASURE(S): Before and after treatment, standardized semen and blood samples were obtained for determinations of sperm concentration, motility, and morphology according to World Health Organization guidelines; semen morphology according to strict criteria; and blood folate and zinc concentrations. Effects of the four interventions were evaluated separately in subfertile and fertile men. RESULT(S): Subfertile men demonstrated a significant 74% increase in total normal sperm count and a minor increase of 4% abnormal spermatozoa. A similar trend was observed in fertile men. Pre-intervention concentrations of folate and zinc in blood and seminal plasma did not significantly differ between fertile and subfertile men. CONCLUSION(S): Total normal sperm count increases after combined zinc sulfate and folic acid treatment in both subfertile and fertile men. Although the beneficial effect on fertility remains to be established, this finding opens avenues of future fertility research and treatment and may affect public health.

C677T methylenetetrahydrofolate reductase polymorphism interferes with the effects of folic acid and zinc sulfate on sperm concentration.

OBJECTIVE: To determine the frequency of C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism in fertile and subfertile males, and the MTHFR-dependent response of sperm concentration after folic acid and/or zinc sulfate intervention. DESIGN: Double-blind, placebo-controlled intervention study. Two outpatient fertility clinics and nine midwifery practices in The Netherlands. PATIENT(S): One hundred thirteen fertile and 77 subfertile males. Daily capsules of folic acid (5 mg) and/or zinc sulfate (66 mg), or placebo for 26 weeks. MAIN OUTCOME MEASURE(S): Prevalence of C677T MTHFR polymorphism and the response of sperm concentration related to MTHFR carriership after intervention treatment. RESULT(S): The C677T methylenetetrahydrofolate reductase genotypes were comparable in fertile and subfertile males. Independent of fertility state, sperm concentration significantly increased in wild-types after folic acid and zinc sulfate treatment only. Heterozygotes and homozygotes did not significantly benefit from either treatment. CONCLUSION(S): C677T methylenetetrahydrofolate reductase polymorphism is not a risk factor for male factor subfertility. In contrast to heterozygotes and homozygotes for C677T MTHFR polymorphism, sperm concentration in wild-types significantly improved after folic acid and zinc sulfate intervention. A stronger role of other folate genes on spermatogenesis is suggested.

Glutathione and glutathione S-transferases A1-1 and P1-1 in seminal plasma may play a role in protecting against oxidative damage to spermatozoa.

OBJECTIVE: To study the levels of glutathione, glutathione S-transferase A1-1, and glutathione S-transferase P1-1 in seminal fluid of fertile and subfertile men. DESIGN: Retrospective case-control study. SETTING: Departments of gastroenterology, obstetrics and gynecology, and epidemiology and biostatistics in a university medical center. PATIENT(S): Twenty-five subfertile men visiting the fertility clinic and 25 fertile men from midwife practices were recruited. INTERVENTION(S): Collection of semen of subfertile and fertile men. MAIN OUTCOME MEASURE(S): Plasma levels of glutathione and glutathione S-transferases A1-1 and P1-1 in relation to seminal characteristics. RESULT(S): Glutathione, glutathione S-transferase A1-1, as well as glutathione S-transferase P1-1 were found in considerable amounts in seminal fluid of subfertile and fertile men. No differences between groups were found for glutathione S-transferases A1-1 and P1-1. Also, no associations with sperm count, motility, or morphology could be detected. Fertile men had significantly higher glutathione levels as compared with the case of subfertile men. Associations of glutathione with sperm motility quality (r(s) = 0.321) and abnormal sperm morphology (r(s) = -0.496) were found. CONCLUSION(S): The presence of glutathione S-transferases A1-1 and P1-1 in seminal fluid suggests a role in the protection against (oxidative) damage of spermatozoa, whereas glutathione may play a role in male fertility.