Impact of COVID-19 vaccination on seminal and systemic inflammation in men.

Expedited development of SARS-CoV-2 vaccines led to public concerns regarding impacts of the novel vaccine on gametes in patients seeking assisted reproduction. In cases of an acute intermittent illness or fever in men, it is often advised to postpone ART treatments so that efforts can be made to enhance wellbeing and improve sperm parameters. However, it is unknown whether sperm parameters are altered in the acute (24-72 hour) phase following COVID-19 vaccination. We performed a longitudinal cohort study of 17 normospermic male patients attending a fertility clinic for semen analysis. Semen and matched peripheral blood samples were collected prior to vaccination, within 46 + 18.9 hours of vaccine course completion (acute) and at 88.4 + 12 days (3 months) post-vaccination. No overall change from baseline was seen in symptoms, mean volume, pH, sperm concentration, motility, morphology or DNA damage in the acute or long phase. Seminal plasma was found to be negative for anti-SARS-CoV2 Spike antibody detection, and MCP-1 levels showed an acute but transient elevation post-vaccine, while IL-8 was marginally increased 3 months after completion of vaccination. A modest, positive correlation was noted between serum levels of the anti-inflammatory cytokine IL-10 and self-reported symptoms post-vaccine. Our findings are reassuring in that no significant adverse effect of vaccination was noted and provide evidence to support the current recommendations of reproductive medicine organisations regarding timing of vaccination during fertility treatment.

N-glycans from serum IgG and total serum glycoproteins specific for endometriosis.

Endometriosis is a chronic inflammatory gynaecological disease characterized by the growth of endometrial tissue outside the uterine cavity. There are currently no definitive non-invasive diagnostic tools. Glycosylation is the most common posttranslational modification of proteins and altered glycosylation has been found in many diseases, including chronic inflammatory conditions and cancer. Sialylation and galactosylation on serum IgG have previously been found to be altered in endometriosis and serum sialylation changed after Zoladex (Goserelin Acetate) therapy. Using IgG and whole serum glycoproteins, we investigated N-glycosylation in two clinical cohorts of women with and without endometriosis. PNGase F-digested serum samples were fluorescently labelled and N-glycans were profiled by ultra-performance liquid chromatography. Clinical data was collected to link glycomic findings with metabolic and hormonal profiles. Total serum glycoprotein and IgG glycosylation differed in patients with endometriosis compared to control cases. The most significantly altered was glycan peak 3 from IgG, containing bisected biantennary glycans, which was decreased in the endometriosis cohorts (p = 0.0000005-0.018). In conclusion, this is the first pilot study to identify changes in N-glycans from whole serum glycoproteins associated with endometriosis. A larger validation study is now warranted and such studies should include the follow-up of surgically and pharmacologically treated patients.

Parkinson's and the couple relationship: a qualitative meta-synthesis.

OBJECTIVE: The aim was to synthesise the current qualitative literature on the impact of Parkinson's on the couple relationship, including individual and dyad studies. METHODS: Noblit and Hare's meta-ethnography approach was applied; 19 studies were included in the review following a systematic search of four electronic databases. The studies included experiences of 137 People with Parkinson's and 191 partners. FINDINGS: Analysis produced three themes: (1) Disruption of roles and responsibilities; (2) Challenges to communication and closeness; and (3) Grief, burden, and isolation. The themes are discussed with supporting extracts from the 19 included studies. CONCLUSION: The findings highlight the challenges that couples experience and the individual and relational resources that support coping. Support should be individually tailored to each couple as the impact on the couple may change in response to individual and contextual factors. This review adds further evidence to the case for relationally focused multidisciplinary team input at all stages of Parkinson's disease.

Irish fertility patients' attitudes to pregnancy and risk mitigation strategies during the COVID-19 pandemic.

The effects of COVID-19 on fertility services became evident in early 2020. Fertility treatments were initially suspended following advice from international fertility governing bodies. We performed a web-based study to investigate the attitudes of male and female fertility patients in Ireland, for risk mitigation strategies and pregnancy advice during the first wave of COVID-19. Despite international recommendations and uncertainty regarding COVID-19 and pregnancy, over two thirds of patients continued trying to conceive, while awaiting recommencement of fertility services. When services resumed, the majority were keen to continue fertility treatment. They were agreeable to telemedicine in place of face-to-face consultations. They felt that privacy was maintained and were comfortable signing consent forms via video link. Large numbers, however, strongly disagreed with the no-partner policy for embryo transfer and early pregnancy scanning, highlighting the importance of partner support. Patients felt strongly that fertility treatments should be classified as essential services and that every effort should be made to continue treatments in future pandemics. These results highlight the importance of maintaining fertility services, while adapting to new practices that may be required. The primary concern of the infertility population is the desire for pregnancy and parenthood. This innate human need trumps concerns regarding COVID-19 for the majority of those affected.

Essential role for epithelial HIF-mediated xenophagy in control of Salmonella infection and dissemination.

The intestinal mucosa exists in a state of "physiologic hypoxia," where oxygen tensions are markedly lower than those in other tissues. Intestinal epithelial cells (IECs) have evolved to maintain homeostasis in this austere environment through oxygen-sensitive transcription factors, including hypoxia-inducible factors (HIFs). Using an unbiased chromatin immunoprecipitation (ChIP) screen for HIF-1 targets, we identify autophagy as a major pathway induced by hypoxia in IECs. One important function of autophagy is to defend against intracellular pathogens, termed "xenophagy." Analysis reveals that HIF is a central regulator of autophagy and that in vitro infection of IECs with Salmonella Typhimurium results in induction of HIF transcriptional activity that tracks with the clearance of intracellular Salmonella. Work in vivo demonstrates that IEC-specific deletion of HIF compromises xenophagy and exacerbates bacterial dissemination. These results reveal that the interaction between hypoxia, HIF, and xenophagy is an essential innate immune component for the control of intracellular pathogens.

Mid-luteal uterine artery Doppler indices in the prediction of pregnancy outcome in nulliparous women undergoing assisted reproduction.

Traditionally, the assessment of endometrial receptivity at transvaginal ultrasound scan has been based on the thickness and the morphological appearance of the endometrium. The objective of this study was to prospectively evaluate endometrial thickness (ET), endometrial morphology and uterine artery Doppler parameters prior to assisted reproduction treatment (ART) in the prediction of pregnancy outcome. This was a prospective cohort study. ET, morphology and uterine artery Doppler (UtAD) pulsatility index (PI) and resistance index (RI) were measured in the mid-luteal stage of the menstrual cycle ultrasonographically, timed with urinary luteinizing hormone testing. A total of 50 women were included in the analysis. The clinical pregnancy rate (CPR) per embryo transfer was 42.0% (n = 21/50). Twenty nine women (58.0%) had an unsuccessful outcome. There were no differences in mean ± SD endometrial thickness (ET) (10.0 ± 1.8 mm vs. 10.5 ± 2.4; p = 0.43), or endometrial morphology (100% (n = 21) vs 100% (n = 29); p = 1.00) between the pregnant and not pregnant groups. Similarly, there were no differences in mean ± SD UtAD PI (2.17 ± 0.83 vs. 2.07 ± 0.81; p = 0.67 or mean ± SD UtAD RI (0.84 ± 0.10 vs. 0.81 ± 0.10; p = 0.30). Ultrasonographic endometrial assessment did not differentiate between those who would have a subsequent clinical pregnancy.

Managing endometrioma to optimize future fertility.

The management of endometriomas in women wishing to preserve their fertility is complex. While surgery can help to achieve pregnancy in some, it may also have a detrimental effect on a woman's ovarian reserve. The present article reviews the impact of endometriomas on fertility and the different management approaches that should be considered in women who wish to preserve their fertility. This study also reviews the role of assisted reproduction in the setting of endometriomas, and the evolving role of oocyte cryopreservation for this benign but progressive disease. Using evidence from the latest guidelines and major publications, we emphasize the need to consider the woman's future fertility when navigating the diverse range of management strategies available, and outline an evidence-based framework to help facilitate fertility-friendly discussion, counseling and management of this complex disease.

Novel diagnostic options for endometriosis - Based on the glycome and microbiome.

Background: Endometriosis is a chronic gynaecological disease whose aetiology is still unknown. Despite its prevalence among women of reproductive age, the pathology of the disease has not yet been elucidated and only symptomatic treatment is available. Endometriosis has high latency and diagnostic methods are both limited and invasive. Aim of review: The aim of this review is to summarise minimally invasive or non-invasive diagnostic methods for endometriosis and their diagnostic efficiencies. Furthermore, we discuss the identification and diagnostic potential of novel disease biomarkers of microbial or glycan origin. Key scientific concepts of review: Great efforts have been made to develop minimally invasive or non-invasive diagnostic methods in endometriosis. The problem with most potential biomarker candidates is that they have high accuracy only in cases of severe disease. Therefore, it is necessary to examine other potential biomarkers more closely. Associations between gastrointestinal and genital tract microbial health and endometriosis have been identified. For instance, irritable bowel syndrome is more common in women with endometriosis, and hormonal imbalance has a negative impact on the microbiome of both the genital tract and the gastrointestinal system. Further interrogation of these associations may have potential diagnostic significance and may identify novel therapeutic avenues. Glycomics may also be a potent source of biomarkers of endometriosis, with a number of glyco-biomarkers already approved by the FDA. Endometriosis-associated microbial and glycomic profiles may represent viable targets for development of innovative diagnostics in this debilitating disease.

Creatine Supplementation for Patients with Inflammatory Bowel Diseases: A Scientific Rationale for a Clinical Trial

Based on theoretical considerations, experimental data with cells in vitro, animal studies in vivo, as well as a single case pilot study with one colitis patient, a consolidated hypothesis can be put forward, stating that "oral supplementation with creatine monohydrate (Cr), a pleiotropic cellular energy precursor, is likely to be effective in inducing a favorable response and/or remission in patients with inflammatory bowel diseases (IBD), like ulcerative colitis and/or Crohn's disease". A current pilot clinical trial that incorporates the use of oral Cr at a dose of 2 × 7 g per day, over an initial period of 2 months in conjunction with ongoing therapies (NCT02463305) will be informative for the proposed larger, more long-term Cr supplementation study of 2 × 3-5 g of Cr per day for a time of 3-6 months. This strategy should be insightful to the potential for Cr in reducing or alleviating the symptoms of IBD. Supplementation with chemically pure Cr, a natural nutritional supplement, is well tolerated not only by healthy subjects, but also by patients with diverse neuromuscular diseases. If the outcome of such a clinical pilot study with Cr as monotherapy or in conjunction with metformin were positive, oral Cr supplementation could then be used in the future as potentially useful adjuvant therapeutic intervention for patients with IBD, preferably together with standard medication used for treating patients with chronic ulcerative colitis and/or Crohn's disease.

The impact of accurately timed mid-luteal endometrial injury in nulligravid women undergoing their first or second embryo transfer.

INTRODUCTION: Endometrial injury or 'scratch' preceding an assisted reproductive therapy (ART) cycle has recently been shown not to improve livebirth rates among women undergoing ART. The objective of this study was to compare pregnancy outcomes in nulliparous women who underwent an accurately timed mid-luteal scratch biopsy prior to ART with those who did not. METHODS: This was a prospective cohort study. Women were recruited between October 2016 and February 2018 inclusive. Women who met the inclusion criteria and who did not undergo an endometrial scratch in the study period were used as a comparison group. Patients underwent a cycle of ART in the menstrual cycle following endometrial scratch. RESULTS: Ninety-eight women were eligible for participation in the study. There were no differences in rates of implantation (35.7% (n = 20/56) vs. 35.4% (n = 17/48); p = 1.00), clinical pregnancy (40.0% (n = 20/50) vs. 39.5% (n = 17/43); p = 1.00) or live birth (34.0% (n = 17/50) vs. 25.6% (n = 11/43); p = 0.50) per embryo transfer between those who underwent a scratch and those who did not. CONCLUSION: Endometrial scratch is a simple, inexpensive and low-risk procedure. However, in this relatively small cohort study, no differences in rates of implantation, clinical pregnancy or live birth in women with primary infertility were determined between those who underwent a scratch and those who did not.

Influence of body mass index on the relationship between endometrial thickness and pregnancy outcome in single blastocyst frozen embryo transfer cycles.

To date there is limited published data assessing whether body mass index (BMI) influences endometrial thickness (ET) and whether this impacts on pregnancy outcomes in single blastocyst FET cycles. The objective of this study, therefore, was to examine the relationship between BMI and ET on the outcome of single blastocyst FET cycles over a five-year period from 2012 until 2016. Patient age, BMI, endometrial pattern and ET prior to FET were recorded. Pregnancy outcomes included: implantation rate, clinical pregnancy rate and live birth rate. A total of 464 cycles met the inclusion criteria and the female age was 36.0 ± 3.0 years (mean ± SD). The mean ± SD BMI was 23.3 ± 3.1 kg/m2 and median ± SD ET was 8.1 ± 1.5 mm. BMI and ET were modestly correlated (Pearson r = 0.244) and there was an association between higher BMI category and higher median ET (7.2, 8.0, 8.3, 8.9 mm; p < 0.001). However, there was no association between ET and pregnancy outcome, either unadjusted, or adjusted for BMI, age, endometrial pattern or embryo quality. The data suggests that although ET increases with increasing BMI, there are no differences in cycle outcome. Importantly, this implies that an ET <8 mm may not jeopardize pregnancy outcome in women with lower BMI. The development of a norm referenced test for BMI and ET may prove to be a helpful adjunct in the clinical IVF setting.

Epithelial HIF-1α/claudin-1 axis regulates barrier dysfunction in eosinophilic esophagitis.

Epithelial barrier dysfunction is a significant factor in many allergic diseases, including eosinophilic esophagitis (EoE). Infiltrating leukocytes and tissue adaptations increase metabolic demands and decrease oxygen availability at barrier surfaces. Understanding of how these processes impact barrier is limited, particularly in allergy. Here, we identified a regulatory axis whereby the oxygen-sensing transcription factor HIF-1α orchestrated epithelial barrier integrity, selectively controlling tight junction CLDN1 (claudin-1). Prolonged experimental hypoxia or HIF1A knockdown suppressed HIF-1α-dependent claudin-1 expression and epithelial barrier function, as documented in 3D organotypic epithelial cultures. L2-IL5OXA mice with EoE-relevant allergic inflammation displayed localized eosinophil oxygen metabolism, tissue hypoxia, and impaired claudin-1 barrier via repression of HIF-1α/claudin-1 signaling, which was restored by transgenic expression of esophageal epithelial-targeted stabilized HIF-1α. EoE patient biopsy analysis identified a repressed HIF-1α/claudin-1 axis, which was restored via pharmacologic HIF-1α stabilization ex vivo. Collectively, these studies reveal HIF-1α's critical role in maintaining barrier and highlight the HIF-1α/claudin-1 axis as a potential therapeutic target for EoE.

Hypoxanthine is a checkpoint stress metabolite in colonic epithelial energy modulation and barrier function.

Intestinal epithelial cells form a selectively permeable barrier to protect colon tissues from luminal microbiota and antigens and to mediate nutrient, fluid, and waste flux in the intestinal tract. Dysregulation of the epithelial cell barrier coincides with profound shifts in metabolic energy, especially in the colon, which exists in an energetically depleting state of physiological hypoxia. However, studies that systematically examine energy flux and adenylate metabolism during intestinal epithelial barrier development and restoration after disruption are lacking. Here, to delineate barrier-related energy flux, we developed an HPLC-based profiling method to track changes in energy flux and adenylate metabolites during barrier development and restoration. Cultured epithelia exhibited pooling of phosphocreatine and maintained ATP during barrier development. EDTA-induced epithelial barrier disruption revealed that hypoxanthine levels correlated with barrier resistance. Further studies uncovered that hypoxanthine supplementation improves barrier function and wound healing and that hypoxanthine appears to do so by increasing intracellular ATP, which improved cytoskeletal G- to F-actin polymerization. Hypoxanthine supplementation increased the adenylate energy charge in the murine colon, indicating potential to regulate adenylate energy charge-mediated metabolism in intestinal epithelial cells. Moreover, experiments in a murine colitis model disclosed that hypoxanthine loss during active inflammation correlates with markers of disease severity. In summary, our results indicate that hypoxanthine modulates energy metabolism in intestinal epithelial cells and is critical for intestinal barrier function.

Uterine natural killer cell progenitor populations predict successful implantation in women with endometriosis-associated infertility.

PROBLEM: Uterine natural killer (uNK) cells play a critical role early in gestation. As we previously identified altered uNK cell development in endometriosis-associated infertility, we herein sought to characterize natural killer (NK) cell profiles in endometriosis that may predict embryo implantation. METHOD OF STUDY: Study participants had a surgical diagnosis of endometriosis-associated infertility. Endometrial tissue and peripheral blood were obtained from 58 women. Thirty-three patients underwent artificial reproductive technology (IVF, ICSI, or IUI) within a mean of 9.5 months of surgery. NK and hematopoietic progenitor cells from endometrium and blood were analyzed by flow cytometry. Successful implantation was defined as a positive pregnancy test. RESULTS: In successful implantation, populations of endometrial CD34+ hematopoietic stem cells were higher (3.97% vs 0.69%; P < .0004), and coexpression of NK cell marker CD56 was increased (81.1% vs 60.9%; P < .034) compared with patients who had failed implantation. In contrast, levels of blood NK progenitors were similar in both groups. CONCLUSION: Our study revealed that uterine NK progenitor cell populations are markedly different in patients with endometriosis who proceed to successful or failed embryo implantation and may define a novel predictor of implantation success. Our findings also highlight the fundamental differences inherent in NK cell repertoires between blood and uterine compartments.

What women want? A scoping survey on women's knowledge, attitudes and behaviours towards ovarian reserve testing and egg freezing.

OBJECTIVE: We aimed to investigate women's knowledge, attitudes and behaviours towards ovarian reserve testing and egg freezing for non-medical reasons in the general population. STUDY DESIGN: This was a cross-sectional survey study of 663 women aged 18-44 years which assessed female perception of ovarian reserve testing and oocyte cryopreservation. An online forum was used to deliver the survey through the use of two social media sites. Participants were recruited through the technique of "snowballing", whereby existing study subjects recruited others from among their acquaintances. The data collected was analyzed using SPSS to explore descriptive statistics and frequencies relating to the participants' knowledge, attitudes and behaviour towards the practices of ovarian reserve testing and oocyte cryopreservation. Categorical variables were analyzed using Chi-squared; a p-value of <0.05 was considered significant. RESULTS: A majority (60%) of women surveyed had knowledge of ovarian reserve testing. 64.8% would be interested in having testing performed. Younger women (<30 years of age) were more interested in checking their ovarian reserve (75.8% vs. 59.1%, p<0.0001). Single women were also more likely to be interested, (73.6% v's 62.1%, p=0.022). 89.7% of women surveyed were aware of oocyte cryopreservation. 72.2% agreed that they would consider freezing their eggs to preserve fertility. There was no significant difference in the numbers of single women compared to women in a relationship who would consider egg freezing to preserve fertility (75.7% v's 71.2%, p=0.347, or in younger (<30years) compared to older women, (74.7% v's 71.1%, p=0.387). A majority (62.1%) of study participants believed that it is a woman's right to postpone pregnancy for social reasons and to freeze her eggs, with no significant difference in options noted between younger and older women. CONCLUSIONS: Knowledge of ovarian reserve testing and oocyte cryopreservation for non-medical reasons were higher than in previous studies, possibly reflecting increasing awareness of these issues among the general public. Additionally, we demonstrated that the women, in our study, were very open to the use of these modern technologies in an attempt to avoid unintended childlessness.

Epithelial Barrier Regulation by Hypoxia-Inducible Factor.

Mucosal tissues represent surfaces that are exposed to the outside world and provide a conduit for internal and external communication. Tissues such as the intestine and the lung are lined by layer(s) of epithelial cells that, when organized in three dimensions, provide a critical barrier to the flux of luminal contents. This selective barrier is provided through the regulated expression of junctional proteins and mucins. Tissue oxygen metabolism is central to the maintenance of homeostasis in the mucosa. In some organs (e.g., the colon), low baseline Po2 determines tissue metabolism and results in basal expression of the transcription factor, hypoxia-inducible factor (HIF), which is enhanced after ischemia/inflammation. Recent studies have indicated that HIF contributes fundamentally to the expression of barrier-related genes and in the regulation of barrier-adaptive responses within the mucosa. Here, we briefly review recent literature on the topic of hypoxia and HIF regulation of barrier in mucosal health and during disease.

Perturbation of neddylation-dependent NF-κB responses in the intestinal epithelium drives apoptosis and inhibits resolution of mucosal inflammation.

Recent work has revealed a central role for neddylation (the conjugation of a Nedd8-moiety to Cullin proteins) in the fine tuning of the NF-κB response (via Cullin-1). In the present study, we investigated the contribution of Cullin-1 neddylation and NF-κB signaling to mucosal inflammatory responses in vitro and in vivo. Initial in vitro studies using cultured intestinal epithelial cells revealed that the neddylation inhibitor MLN4924 prominently induces the deneddylation of Cullin-1. Parallel western blot, luciferase reporter and gene target assays identified MLN4924 as a potent inhibitor of intestinal epithelial NF-κB. Subsequent studies revealed that MLN4924 potently induces epithelial apoptosis but only in the presence of additional inflammatory stimuli. In vivo administration of MLN4924 (3 mg/kg/d) in a TNBS-induce colitis model significantly accentuated disease severity. Indeed, MLN4924 resulted in worsened clinical scores and increased mortality early in the inflammatory response. Histologic analysis of the colon revealed that neddylation inhibition results in increased tissue damage and significantly increased mucosal apoptosis as determined by TUNEL and cleaved caspase-3 staining, particularly prominent within the epithelium. Extensions of these studies revealed that ongoing inflammation is associated with significant loss of deneddylase-1 (SENP8) expresssion. These studies reveal that intact Cullin-1 neddylation is central to resolution of acute inflammation.

Oxygen metabolism and barrier regulation in the intestinal mucosa.

Mucosal surfaces are lined by epithelial cells and provide an important barrier to the flux of antigens from the outside. This barrier is provided at a number of levels, including epithelial junctional complexes, mucus production, and mucosa-derived antimicrobials. Tissue metabolism is central to the maintenance of homeostasis in the mucosa. In the intestine, for example, baseline pO2 levels are uniquely low due to counter-current blood flow and the presence of large numbers of bacteria. As such, hypoxia and HIF signaling predominates normal intestinal metabolism and barrier regulation during both homeostasis and active inflammation. Contributing factors that elicit important adaptive responses within the mucosa include the transcriptional regulation of tight junction proteins, metabolic regulation of barrier components, and changes in autophagic flux. Here, we review recent literature around the topic of hypoxia and barrier function in health and during disease.

Inflammatory Bowel Disease: Influence and Implications in Reproduction.

The incidence and prevalence of inflammatory bowel disease (IBD) continues to rise with time, signifying its emergence as a global disease. Clinical onset of IBD, comprising Crohn's disease and ulcerative colitis, typically occurs before or at peak reproductive age. Although active disease in female patients is associated with reduced fertility and adverse obstetric outcomes in pregnancy, the molecular mechanisms underlying this altered reproductive course, and its impact on IBD transmission to offspring, remain poorly understood. Clinical and experimental studies have now begun to elucidate the hormonal, environmental, and microbial factors that modulate immune-reproductive cross talk in IBD and define their impact on maternal health, fetal development, and heritability of disease risk. Evolving insight into maternal-fetal imprinting in IBD has important implications for patient counseling and disease management during pregnancy and may help predict clinical outcomes for both mother and child.

Creatine kinase in ischemic and inflammatory disorders.

The creatine/phosphocreatine pathway plays a conserved and central role in energy metabolism. Compartmentalization of specific creatine kinase enzymes permits buffering of local high energy phosphates in a thermodynamically favorable manner, enabling both rapid energy storage and energy transfer within the cell. Augmentation of this metabolic pathway by nutritional creatine supplementation has been shown to elicit beneficial effects in a number of diverse pathologies, particularly those that incur tissue ischemia, hypoxia or oxidative stress. In these settings, creatine and phosphocreatine prevent depletion of intracellular ATP and internal acidification, enhance post-ischemic recovery of protein synthesis and promote free radical scavenging and stabilization of cellular membranes. The creatine kinase energy system is itself further regulated by hypoxic signaling, highlighting the existence of endogenous mechanisms in mammals that can enhance creatine metabolism during oxygen deprivation to promote tissue resolution and homeostasis. Here, we review recent insights into the creatine kinase pathway, and provide rationale for dietary creatine supplementation in human ischemic and inflammatory pathologies.