Blood pressure and lipid profiles in children born after ART with frozen embryo transfer.

STUDY QUESTION: Are blood pressure (BP) and lipid profiles different between children conceived after ART with frozen embryo transfer (FET), fresh embryo transfer (fresh-ET), and natural conception (NC)? SUMMARY ANSWER: Girls conceived after FET had significantly higher systolic BP and heart rate compared with girls born after fresh-ET; boys conceived after FET had a slightly more favourable lipid profile compared with boys born after fresh-ET and NC. WHAT IS KNOWN ALREADY: Children conceived after ART with FET are more often born large for gestational age (LGA). LGA in general increases the risk of obesity, diabetes, and cardiovascular disease later in life. Studies on mice and humans on the whole ART population have raised concerns about premature vascular ageing and higher BP. The cardiovascular health of children born after FET is scarcely explored and the results are diverging. STUDY DESIGN SIZE DURATION: This study was part of the cohort study 'Health in Childhood following Assisted Reproductive Technology' (HiCART), which included 606 singletons (292 boys) born between December 2009 and December 2013: 200 children were conceived after FET; 203 children were conceived after fresh-ET; and 203 children were conceived naturally and matched for birth year and sex. The study period lasted from January 2019 to September 2021. PARTICIPANTS/MATERIALS SETTING METHODS: The included children were 7-10 years of age at examination and underwent a clinical examination with anthropometric measurements, pubertal staging, and BP measurement. Additionally, a fasting blood sample was collected and analysed for cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL), and triglycerides. Systolic and diastolic BP were converted to standard deviation scores (SDS) using an appropriate reference and accounting for height (SDS) of the child. The three study groups were compared pairwise using a univariate linear regression model. Mean differences were adjusted for confounders using multiple linear regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Girls and boys conceived after FET had significantly higher birthweight (SDS) compared with naturally conceived peers (mean difference: girls: 0.35, 95% CI (0.06-0.64), boys: 0.35, 95% CI (0.03-0.68)). Girls conceived after FET had significantly higher systolic BP (SDS) and heart rate compared with girls conceived after fresh-ET (adjusted mean difference: systolic BP (SDS): 0.25 SDS, 95% CI (0.03-0.47), heart rate: 4.53, 95% CI (0.94-8.13)). Regarding lipid profile, no significant differences were found between the three groups of girls. For the boys, no significant differences were found for BP and heart rate. Lipid profiles were more favourable in boys born after FET compared with both boys conceived after fresh-ET and NC. All outcomes were adjusted for parity, maternal BMI at early pregnancy, smoking during pregnancy, educational level, birthweight, breastfeeding, child age at examination, and onset of puberty. LIMITATIONS REASONS FOR CAUTION: The participation rate varied from 18 to 42% in the three groups, and therefore selection bias cannot be excluded. However, extensive non-participant analyses were performed that showed almost no differences in background characteristics between participants and non-participants in the three groups, making selection bias less likely. WIDER IMPLICATIONS OF THE FINDINGS: The higher birthweight in children conceived after FET was associated with increased systolic BP (SDS) and heart rate in girls conceived after FET compared with fresh-ET. This may be an early indicator of compromised long-term cardiovascular health in this group. The study was not powered to investigate these outcomes and further studies are therefore warranted to confirm the findings. STUDY FUNDING/COMPETING INTERESTS: The study was funded by the Novo Nordisk Foundation (grant number: NNF18OC0034092, NFF19OC0054340) and Rigshospitalets Forskningsfond. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT03719703.

Variant in the synaptonemal complex protein SYCE2 associates with pregnancy loss through effect on recombination.

Two-thirds of all human conceptions are lost, in most cases before clinical detection. The lack of detailed understanding of the causes of pregnancy losses constrains focused counseling for future pregnancies. We have previously shown that a missense variant in synaptonemal complex central element protein 2 (SYCE2), in a key residue for the assembly of the synaptonemal complex backbone, associates with recombination traits. Here we show that it also increases risk of pregnancy loss in a genome-wide association analysis on 114,761 women with reported pregnancy loss. We further show that the variant associates with more random placement of crossovers and lower recombination rate in longer chromosomes but higher in the shorter ones. These results support the hypothesis that some pregnancy losses are due to failures in recombination. They further demonstrate that variants with a substantial effect on the quality of recombination can be maintained in the population.

Results from the first autologous grafting of adult human testis tissue: a case report.

Fertility restoration using autologous testicular tissue transplantation is relevant for infertile men surviving from childhood cancer and, possibly, in men with absent or incomplete spermatogenesis resulting in the lack of spermatozoa in the ejaculate (non-obstructive azoospermia, NOA). Currently, testicular tissue from pre-pubertal boys extracted before treatment with gonadotoxic cancer therapy can be cryopreserved with good survival of spermatogonial stem cells. However, strategies for fertility restoration, after successful cancer treatment, are still experimental and no clinical methods have yet been developed. Similarly, no clinically available treatments can help men with NOA to become biological fathers after failed attempts of testicular surgical sperm retrieval. We present a case of a 31-year-old man with NOA who had three pieces of testis tissue (each ∼2 × 4 × 2 mm3) extracted and cryopreserved in relation to performing microdissection testicular sperm extraction (mTESE). Approximately 2 years after mTESE, the thawed tissue pieces were engrafted in surgically created pockets bilaterally under the scrotal skin. Follow-up was performed after 2, 4, and 6 months with assessment of reproductive hormones and ultrasound of the scrotum. After 6 months, all engrafted tissue was extracted and microscopically analyzed for the presence of spermatozoa. Furthermore, parts of the extracted tissue were analyzed histologically and by immunohistochemical analysis. Active blood flow in the engrafted tissue was demonstrated by doppler ultrasound after 6 months. No spermatozoa were found in the extracted tissue. Histological and immunohistochemical analysis demonstrated graft survival with intact clear tubules and normal cell organization. Sertoli cells and spermatocytes with normal morphology were located near the basement membrane. MAGE-A and VASA positive spermatogonia/spermatocytes were detected together with SOX9 positive Sertoli cells. Spermatocytes and/or Sertoli cells positive for γH2AX was also detected. In summary, following autologous grafting of frozen-thawed testis tissue under the scrotal skin in a man with NOA, we demonstrated graft survival after 6 months. No mature spermatozoa were detected; however, this is likely due to the pre-existing spermatogenic failure.

CHK1-CDC25A-CDK1 regulate cell cycle progression and protect genome integrity in early mouse embryos.

After fertilization, remodeling of the oocyte and sperm genomes is essential to convert these highly differentiated and transcriptionally quiescent cells into early cleavage-stage blastomeres that are transcriptionally active and totipotent. This developmental transition is accompanied by cell cycle adaptation, such as lengthening or shortening of the gap phases G1 and G2. However, regulation of these cell cycle changes is poorly understood, especially in mammals. Checkpoint kinase 1 (CHK1) is a protein kinase that regulates cell cycle progression in somatic cells. Here, we show that CHK1 regulates cell cycle progression in early mouse embryos by restraining CDK1 kinase activity due to CDC25A phosphatase degradation. CHK1 kinase also ensures the long G2 phase needed for genome activation and reprogramming gene expression in two-cell stage mouse embryos. Finally, Chk1 depletion leads to DNA damage and chromosome segregation errors that result in aneuploidy and infertility.

Fancm has dual roles in the limiting of meiotic crossovers and germ cell maintenance in mammals.

Meiotic crossovers are required for accurate chromosome segregation and producing new allelic combinations. Meiotic crossover numbers are tightly regulated within a narrow range, despite an excess of initiating DNA double-strand breaks. Here, we reveal the tumor suppressor FANCM as a meiotic anti-crossover factor in mammals. We use unique large-scale crossover analyses with both single-gamete sequencing and pedigree-based bulk-sequencing datasets to identify a genome-wide increase in crossover frequencies in Fancm-deficient mice. Gametogenesis is heavily perturbed in Fancm loss-of-function mice, which is consistent with the reproductive defects reported in humans with biallelic FANCM mutations. A portion of the gametogenesis defects can be attributed to the cGAS-STING pathway after birth. Despite the gametogenesis phenotypes in Fancm mutants, both sexes are capable of producing offspring. We propose that the anti-crossover function and role in gametogenesis of Fancm are separable and will inform diagnostic pathways for human genomic instability disorders.

Relatives' negotiations with healthcare professionals during older people's admission in an emergency department: An ethnographic study.

BACKGROUND: Relatives are recognised as important for older patients' care and treatment. Variations in relatives' opportunities to negotiate the quality and continuity of older people's care and treatment can potentially lead to inequality in older people's access to care and treatment. AIM: This study aimed to examine relatives' opportunities and strategies for negotiation with health care professionals (HCPs) during the admission of older people to emergency departments in Denmark. MATERIALS AND METHODS: We planned a qualitative ethnographical study employing a hermeneutic approach. Observations focused on social situations and interactions between relatives and HCPs. The analysis was guided by qualitative content analysis. RESULTS: The analysis derived one main theme, attitude to action, containing three subthemes: frustration obtaining access, presenting the case and a powerful relationship. Being active appeared to be essential to achieving possibilities for negotiation with HCPs. DISCUSSION: Inspired by Bourdieu, habitus, doxical values and institutional logics of relatives seem to affect their opportunities to negotiate with HCPs during older people's admission to an emergency department. CONCLUSION: Active and proactive relatives seem to have better opportunities to negotiate with HCPs during older people's acute hospital admission than reactive, passive and hesitant relatives. The logic of public management and the medical profession seem to dominate and influence doxa in the EDs and put special demands on the relatives. This imbalance constitutes a risk of inequality in older people's access to health.

Penetrance of pathogenic genetic variants associated with premature ovarian insufficiency.

Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ~100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.14%) of whom reported at natural menopause under the age of 40 years. We found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes, we ruled out even modest penetrance, with 99.9% (13,699 out of 13,708) of all protein-truncating variants found in reproductively healthy women. We found evidence of haploinsufficiency effects in several genes, including TWNK (1.54 years earlier menopause, P = 1.59 × 10-6) and SOHLH2 (3.48 years earlier menopause, P = 1.03 × 10-4). Collectively, our results suggest that, for the vast majority of women, POI is not caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels. Our findings, plus previous studies, suggest that most POI cases are likely oligogenic or polygenic in nature, which has important implications for future clinical genetic studies, and genetic counseling for families affected by POI.

Childhood BMI after ART with frozen embryo transfer.

STUDY QUESTION: Does BMI at 7-10 years of age differ in children conceived after frozen embryo transfer (FET) compared to children conceived after fresh embryo transfer (fresh-ET) or natural conception (NC)? SUMMARY ANSWER: BMI in childhood does not differ between children conceived after FET compared to children conceived after fresh-ET or NC. WHAT IS KNOWN ALREADY: High childhood BMI is strongly associated with obesity and cardiometabolic disease and mortality in adulthood. Children conceived after FET have a higher risk of being born large for gestational age (LGA) than children conceived after NC. It is well-documented that being born LGA is associated with an increased risk of obesity in childhood, and it has been hypothesized that ART induces epigenetic variations around fertilization, implantation, and early embryonic stages, which influence fetal size at birth as well as BMI and health later in life. STUDY DESIGN, SIZE, DURATION: The study 'Health in Childhood following Assisted Reproductive Technology' (HiCART) is a large retrospective cohort study with 606 singletons aged 7-10 years divided into three groups according to mode of conception: FET (n = 200), fresh-ET (n = 203), and NC (n = 203). All children were born in Eastern Denmark from 2009 to 2013 and the study was conducted from January 2019 to September 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: We anticipated that the participation rate would differ between the three study groups owing to variation in the motivation to engage. To reach the goal of 200 children in each group, we invited 478 in the FET-group, 661 in the fresh-ET-group, and 1175 in the NC-group. The children underwent clinical examinations including anthropometric measurements, whole-body dual-energy x-ray absorptiometry-scan, and pubertal staging. Standard deviation scores (SDS) were calculated for all anthropometric measurements using Danish reference values. Parents completed a questionnaire regarding the pregnancy and the current health of the child and themselves. Maternal, obstetric, and neonatal data were obtained from the Danish IVF Registry and Danish Medical Birth Registry. MAIN RESULTS AND THE ROLE OF CHANCE: As expected, children conceived after FET had a significantly higher birthweight (SDS) compared to both children born after fresh-ET (mean difference 0.42, 95% CI (0.21; 0.62)) and NC (mean difference 0.35, 95% CI (0.14; 0.57)). At follow-up (7-10 years), no differences were found in BMI (SDS) comparing FET to fresh-ET, FET to NC, and fresh-ET to NC. Similar results were also found regarding the secondary outcomes weight (SDS), height (SDS), sitting height, waist circumference, hip circumference, fat, and fat percentage. In the multivariate linear regression analyses, the effect of mode of conception remained non-significant after adjusting for multiple confounders. When stratified on sex, weight (SDS), and height (SDS) were significantly higher for girls born after FET compared to girls born after NC. Further, FET-girls also had significantly higher waist, hip, and fat measurements compared to girls born after fresh-ET. However, for the boys the differences remained insignificant after confounder adjustment. LIMITATIONS, REASONS FOR CAUTION: The sample size was decided in order to detect a difference of 0.3 SDS in childhood BMI (which corresponds to an adult cardiovascular mortality hazard ratio of 1.034). Thus, smaller differences in BMI SDS may be overlooked. As the overall participation rate was 26% (FET: 41%, fresh-ET: 31%, NC: 18%), selection bias cannot be excluded. Regarding the three study groups, many possible confounders have been included but there might be a small risk of selection bias as information regarding cause of infertility is not available in this study. WIDER IMPLICATIONS OF THE FINDINGS: The increased birthweight in children conceived after FET did not translate into differences in BMI, however, for the girls born after FET, we observed increased height (SDS) and weight (SDS) compared to the girls born after NC, while for the boys the results remained insignificant after confounder adjustment. Since body composition in childhood is a strong biomarker of cardiometabolic disease later in life, longitudinal studies of girls and boys born after FET are needed. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Novo Nordisk Foundation (grant number: NNF18OC0034092, NFF19OC0054340) and Rigshospitalets Research Foundation. There were no competing interests. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT03719703.

Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus.

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.

Pan-cancer association of DNA repair deficiencies with whole-genome mutational patterns.

DNA repair deficiencies in cancers may result in characteristic mutational patterns, as exemplified by deficiency of BRCA1/2 and efficacy prediction for PARP inhibitors. We trained and evaluated predictive models for loss-of-function (LOF) of 145 individual DNA damage response genes based on genome-wide mutational patterns, including structural variants, indels, and base-substitution signatures. We identified 24 genes whose deficiency could be predicted with good accuracy, including expected mutational patterns for BRCA1/2, MSH3/6, TP53, and CDK12 LOF variants. CDK12 is associated with tandem duplications, and we here demonstrate that this association can accurately predict gene deficiency in prostate cancers (area under the receiver operator characteristic curve = 0.97). Our novel associations include mono- or biallelic LOF variants of ATRX, IDH1, HERC2, CDKN2A, PTEN, and SMARCA4, and our systematic approach yielded a catalogue of predictive models, which may provide targets for further research and development of treatment, and potentially help guide therapy.

Many different aspects of the environment ­ such as ultraviolet radiation, carcinogens in food and drink, and the ageing process itself ­ damage the DNA in human cells. Normally, cells can repair these sites by activating a mechanism known as the DNA damage response. However, the hundreds of genes that orchestrate this response are also themselves often lost or damaged, allowing the unrepaired sites to turn into permanent mutations that accumulate across the genome of the cancer cell. By studying the DNA of cancer cells, it has been possible to identify characteristic patterns of mutations, called mutational signatures, that appear in different types of cancer. One specific pattern has been linked to the loss of either the BRCA1 or BRCA2 gene, both of which are part of the DNA damage response. However, it remained unclear how many other genes involved in the DNA damage response also lead to detectable mutational signatures when lost. To investigate, Sørensen et al. computationally analysed data from over six thousand cancer patients. They looked for associations between over 700 DNA damage response genes and 80 different mutational signatures. As expected, the analysis revealed a strong connection between the loss of BRCA1/BRCA2 and their known mutational signature. However, it also found 23 other associations between DNA damage response genes that had been lost or damaged and particular patterns of mutations in a variety of cancers. These findings suggest that mutational signatures could be used more widely to predict which DNA damage response genes are no longer functioning in the genome of cancer cells. The mutational signature caused by the loss of BRAC1/BRAC2 has been shown to make patients more responsive to a certain type of chemotherapy. Further experiments are needed to determine whether the connections identified by Sørensen et al. could also provide information on which treatment would benefit a cancer patient the most. In the future, this might help medical practitioners provide more personalized treatment.

Cell-free fetal DNA for genetic evaluation in Copenhagen Pregnancy Loss Study (COPL): a prospective cohort study.

BACKGROUND: One in four pregnancies end in a pregnancy loss. Although the effect on couples is well documented, evidence-based treatments and prediction models are absent. Fetal aneuploidy is associated with a higher chance of a next successful pregnancy compared with euploid pregnancy loss in which underlying maternal conditions might be causal. Ploidy diagnostics are therefore advantageous but challenging as they require collection of the pregnancy tissue. Cell-free fetal DNA (cffDNA) from maternal blood has the potential for evaluation of fetal ploidy status, but no large-scale validation of the method has been done. METHODS: In this prospective cohort study, women with a pregnancy loss were recruited as a part of the Copenhagen Pregnancy Loss (COPL) study from three gynaecological clinics at public hospitals in Denmark. Women were eligible for inclusion if older than 18 years with a pregnancy loss before gestational age 22 weeks (ie, 154 days) and with an intrauterine pregnancy confirmed by ultrasound (including anembryonic sac), and women with pregnancies of unknown location or molar pregnancies were excluded. Maternal blood was collected while pregnancy tissue was still in situ or within 24 h after pregnancy tissue had passed and was analysed by genome-wide sequencing of cffDNA. Direct sequencing of the pregnancy tissue was done as reference. FINDINGS: We included 1000 consecutive women, at the time of a pregnancy loss diagnosis, between Nov 12, 2020, and May 1, 2022. Results from the first 333 women with a pregnancy loss (recruited between Nov 12, 2020, and Aug 14, 2021) were used to evaluate the validity of cffDNA-based testing. Results from the other 667 women were included to evaluate cffDNA performance and result distribution in a larger cohort of 1000 women in total. Gestational age of fetus ranged from 35-149 days (mean of 70·5 days [SD 16·5], or 10 weeks plus 1 day). The cffDNA-based test had a sensitivity for aneuploidy detection of 85% (95% CI 79-90) and a specificity of 93% (95% CI 88-96) compared with direct sequencing of the pregnancy tissue. Among 1000 cffDNA-based test results, 446 (45%) were euploid, 405 (41%) aneuploid, 37 (4%) had multiple aneuploidies, and 112 (11%) were inconclusive. 105 (32%) of 333 women either did not manage to collect the pregnancy tissue or collected a sample classified as unknown tissue giving a high risk of being maternal. INTERPRETATION: This validation of cffDNA-based testing in pregnancy loss shows the potential and feasibility of the method to distinguish euploid and aneuploid pregnancy loss for improved clinical management and benefit of future reproductive medicine and women's health research. FUNDING: Ole Kirks Foundation, BioInnovation Institute Foundation, and the Novo Nordisk Foundation.

Errors of the Egg: The Establishment and Progression of Human Aneuploidy Research in the Maternal Germline.

Meiosis, a key process in the creation of haploid gametes, is a complex cellular division incorporating unique timing and intricate chromosome dynamics. Abnormalities in this elaborate dance can lead to the production of aneuploid gametes, i.e., eggs containing an incorrect number of chromosomes, many of which cannot generate a viable pregnancy. For many decades, research has been attempting to address why this process is notoriously error prone in humans compared to many other organisms. Rapidly developing technologies, access to new clinical material, and a mounting public infertility crisis have kept the field both active and quickly evolving. In this review, we discuss the history of aneuploidy in humans with a focus on its origins in maternal meiosis. We also gather current working mechanistic hypotheses, as well as up-and-coming areas of interest that point to future scientific avenues and their potential clinical applications.

Maternal exome analysis for the diagnosis of oocyte maturation defects and early embryonic developmental arrest.

RESEARCH QUESTION: Can a methodology be developed for case selection and whole-exome sequencing (WES) analysis of women who are infertile owing to recurrent oocyte maturation defects (OOMD) and/or preimplantation embryo lethality (PREMBL)? DESIGN: Data were collected from IVF patients attending the Istanbul Memorial Hospital (2015-2021). A statistical methodology to identify infertile endophenotypes (recurrent low oocyte maturation rate, low fertilization rate and preimplantation developmental arrest) was developed using a large IVF dataset (11,221 couples). Twenty-eight infertile women with OOMD/PREMBL were subsequently enrolled for WES on their genomic DNA. Pathogenic variants were prioritized using a custom-made bioinformatic pipeline set to minimize false-positive discoveries through resampling in control cohorts (the Human Genome Diversity Project and 1343 whole-exome sequences from oocyte donors). Individual single-cell RNA sequencing data from 18 human metaphase II (MII) oocytes and antral granulosa cells was used for genome-wide validation. WES and bioinformatics were performed at Igenomix and the National Research Council, Italy. RESULTS: Variant prioritization analysis identified 265 unique variants in 248 genes (average 22.4 per sample). Of the genes harbouring high-impact variants 78% were expressed by MII oocytes and/or antral granulosa cells, significantly higher than for random sample of controls (odds ratio = 5, Fisher's exact P = 0.0004). Seven of the 28 women (25%) were homozygous carriers of missense pathogenic variants in known candidate genes for OOMD/PREMBL, including PATL2, NLRP5 (n = 2),TLE6, PADI6, TUBB8 and TRIP13. Furthermore, novel gene-disease associations were identified. In fact, one woman with a low oocyte maturation rate was a homozygous carrier of high-impact variants in ENSA, an essential gene for prophase I meiotic transition in mice. CONCLUSIONS: This analytical framework could reveal known and new genes associated with isolated recurrent OOMD/PREMBL, providing essential indications for scaling this strategy to larger studies.

Impact of implementation of the Maternal-Fetal Triage Index on patients presenting with severe hypertension.

BACKGROUND: Severe hypertension remains one of the leading preventable causes of maternal mortality in the United States. Timeliness to response to severe hypertension in pregnancy is a crucial quality indicator tracked by state and national organizations. We hypothesized that the implementation of the Maternal-Fetal Triage Index, a validated acuity tool, would improve care performance in women with severe hypertension in an urban, inner-city hospital setting. OBJECTIVE: This study aimed to assess the impact of the Maternal-Fetal Triage Index on the management of women presenting with severe preeclampsia diagnosed by severe hypertension as measured by time to provider assessment, administration of magnesium sulfate, and immediate administration of acute antihypertensives. STUDY DESIGN: This was a prospective, observational study of pregnant women presenting to the labor and delivery triage unit with severe preeclampsia diagnosed by severe hypertension giving birth at a large urban inner-city academic facility before (epoch 1: January 1, 2019, to December 31, 2019) and after (epoch 2: March 1, 2021, to September 31, 2021) the implementation of the Maternal-Fetal Triage Index. Baseline outcomes of time to assessment, time to magnesium sulfate prophylaxis, and time to antihypertensive medication administration before the implementation of the Maternal-Fetal Triage Index were assessed. The Maternal-Fetal Triage Index tool was implemented on March 1, 2021, following standardized education in 2020 for all triage nurses, unit technicians, healthcare unit coordinators, and healthcare providers. Time to assessment, administration of magnesium sulfate prophylaxis, and time to antihypertensive administration after the implementation of the Maternal-Fetal Triage Index were compared with measures before the implementation of the Maternal-Fetal Triage Index. Statistical analysis included Wilcoxon rank-sum test with P<.05 considered significant when comparing epoch 1 with epoch 2. RESULTS: A total of 370 patients were admitted with severe hypertension in 2019 before the use of the Maternal-Fetal Triage Index, and 254 patients were admitted with severe hypertension in 2021 after the implementation of the Maternal-Fetal Triage Index. There was no difference between epochs across baseline characteristics, including age, race and ethnicity, parity, and body mass index. After the Maternal-Fetal Triage Index was implemented, the time to provider assessment was significantly improved, from a median time of 44 minutes (interquartile range, 0-65) in epoch 1 to 17 minutes (interquartile range, 0-39) in epoch 2 (P<.001). Furthermore, the time from arrival to magnesium sulfate prophylaxis was significantly faster with a median time of 161 minutes (interquartile range, 109-256) in epoch 1 vs 127 minutes (interquartile range, 85-258) in epoch 2 (P=.001). Moreover, there was a decrease in the time from arrival to antihypertensive medication administration for severe blood pressures after the implementation of the Maternal-Fetal Triage Index (101 minutes [interquartile range, 61-177] vs 66 minutes [interquartile range, 35-203]; P<.001). CONCLUSION: The implementation of the Maternal-Fetal Triage Index at a large urban inner-city hospital was associated with improved timeliness of assessment and treatment of women with severe hypertension. The Maternal-Fetal Triage Index is a viable tool to improve the efficiency in triage units, specifically in the management of severe hypertension.

Characterization and Survival of Human Infant Testicular Cells After Direct Xenotransplantation.

Background: Cryopreservation of prepubertal testicular tissue preserves spermatogonial stem cells (SSCs) that may be used to restore fertility in men at risk of infertility due to gonadotoxic treatments for either a malignant or non-malignant disease. Spermatogonial stem cell-based transplantation is a promising fertility restoration technique. Previously, we performed xenotransplantation of propagated SSCs from prepubertal testis and found human SSCs colonies within the recipient testes six weeks post-transplantation. In order to avoid the propagation step of SSCs in vitro that may cause genetic and epigenetic changes, we performed direct injection of single cell suspension in this study, which potentially may be safer and easier to be applied in future clinical applications. Methods: Testis biopsies were obtained from 11 infant boys (median age 1.3 years, range 0.5-3.5) with cryptorchidism. Following enzymatic digestion, dissociated single-cell suspensions were prelabeled with green fluorescent dye and directly transplanted into seminiferous tubules of busulfan-treated mice. Six to nine weeks post-transplantation, the presence of gonocytes and SSCs was determined by whole-mount immunofluorescence for a number of germ cell markers (MAGEA, GAGE, UCHL1, SALL4, UTF1, and LIN28), somatic cell markers (SOX9, CYP17A1). Results: Following xenotransplantation human infant germ cells, consisting of gonocytes and SSCs, were shown to settle on the basal membrane of the recipient seminiferous tubules and form SSC colonies with expression of MAGEA, GAGE, UCHL1, SALL4, UTF1, and LIN28. The colonization efficiency was approximately 6%. No human Sertoli cells were detected in the recipient mouse testes. Conclusion: Xenotransplantation, without in vitro propagation, of testicular cell suspensions from infant boys with cryptorchidism resulted in colonization of mouse seminiferous tubules six to nine weeks post-transplantation. Spermatogonial stem cell-based transplantation could be a therapeutic treatment for infertility of prepubertal boys with cryptorchidism and boys diagnosed with cancer. However, more studies are required to investigate whether the low number of the transplanted SSC is sufficient to secure the presence of sperm in the ejaculate of those patients over time.

Relatives' experiences of the hospitalisation of older people with COVID-19: A qualitative interview study.

BACKGROUND: During the COVID-19 pandemic, visitors were restricted from hospitals, separating them from hospitalised friends and family to reduce the infection risk. OBJECTIVES: The objective was to explore how relatives of older people acutely admitted to hospital with COVID-19 experienced being a relative, and how they felt about their contact with health care professionals (HCPs) when visitor restrictions prevented their physical presence in the ward. METHOD: This study employed a qualitative design. We used individual qualitative semi-structured interviews and the participants were relatives of acutely admitted older people from three COVID-19 wards in Denmark. A total of 18 relatives participated, 14 female and 4 male, aged between 45 and 83 years. The analysis was guided by Graneheim and Lundman's qualitative content analysis. RESULTS: The analysis derived the following three themes: (1) the importance of trust in a period of uncertainty; (2) the meaning of contact with HCPs, and (3) active but at a distance-a balancing act. The participants' feelings of uncertainty were prominent. The unknown nature of the disease and the unusual situation challenged relatives' trust in HCPs and the health care system. CONCLUSIONS AND RELEVANCE TO PRACTICE: The findings highlight relatives' stress when the possibilities for visiting are restricted and the importance of trust in, and the relationship with HCPs. This study can strengthen HCPs' understanding of relatives' situation when older people are hospitalised during and after the COVID-19 pandemic.

Fertility preservation in boys facing gonadotoxic cancer therapy.

Patient survival following childhood cancer has increased with contemporary radiation and chemotherapy techniques. However, gonadotoxicity associated with treatments means that infertility is a common consequence in survivors. Novel fertility preservation options are emerging, but knowledge about these options amongst urologists and other medical professionals is lacking. Pre-pubertal boys generally do not produce haploid germ cells. Thus, strategies for fertility preservation require cryopreservation of tissue containing spermatogonial stem cells (SSCs). Few centres worldwide routinely offer this option and fertility restoration (including testicular tissue engraftment, autotransplantation of SSCs and in vitro maturation of SSCs to spermatozoa) post-thaw is experimental. In pubertal boys, the main option for fertility preservation is masturbation and cryopreservation of the ejaculate. Assisted ejaculation using penile vibratory stimulation or electroejaculation and surgical sperm retrieval can be used in a sequential manner after failed masturbation. Physicians should inform boys and parents about the gonadotoxic effects of cancer treatment and offer fertility preservation. Preclinical experience has identified challenges in pre-pubertal fertility preservation, but available options are expected to be successful when today's pre-pubertal boys with cancer become adults. By contrast, fertility preservation in pubertal boys is clinically proven and should be offered to all patients undergoing cancer treatment.

Relatives' negotiation power in relation to older people's acute hospital admission: A qualitative interview study.

BACKGROUND: Acutely admitted older people are potentially vulnerable and dependent on relatives to negotiate and navigate on their behalf. AIM: This study aimed to explore relatives' experiences of their interactions with healthcare professionals during acute hospital admission of older people to derive themes of importance for relatives' negotiations with these professionals. METHOD: A qualitative design was applied. Relatives of acutely admitted older people at two emergency departments in Denmark were interviewed (n = 17). The qualitative content analysis was guided by Graneheim and Lundman's concepts. RESULTS: The analysis derived four themes: (a) Mandate, (b) Incentive, (c) Capability and (d) Attitude to taking action. These four sources of relatives' negotiation power can be illustrated in the MICA model. CONCLUSION: Four themes were identified as important sources of relatives' negotiation power. Since the four sources of power potentially change according to the situation, relatives' negotiation power seems to be context dependent.

Impact of cesarean delivery due to maternal choice on perinatal outcome in term nulliparous patients with a singleton fetus in a vertex presentation.

OBJECTIVE: The objectives of our study were to: (1) evaluate the prevalence of cesarean delivery due to maternal request among nulliparous, term, singleton, vertex (NTSV) patients; (2) identify the clinical profile, if any, of these patients; and (3) compare the perinatal outcomes between NTSV patients who requested a cesarean delivery versus patients who did not request cesarean delivery. STUDY DESIGN: This was a retrospective case control study performed at a single institution between November 2018 and July 2019. All NTSV patients who had a cesarean delivery due to maternal choice were identified and compared to the next two NTSV patients in labor who delivered vaginally or by medically indicated cesarean delivery following a cesarean delivery by maternal choice. The primary outcome was composite neonatal morbidity. Secondary outcomes were individual components of composite neonatal and maternal morbidity. RESULTS: Of 1138 NTSV patients, 61 (5.4%) patients opted for cesarean delivery by maternal choice. There were significant differences in the demographic/clinical profile between cases and controls including BMI (35.3 kg/m2 vs. 32.7 kg/m2, p < .01), birthweight (3552 gr vs. 3333 gr, p < .001) and documented mental illness (41.0% vs. 22.1% respectively, p < .01). There was no significant difference in composite neonatal morbidity between cases and controls (6.6% vs. 5.7%, adjusted odds ratio [aOR] 0.96, 95% CI 0.25-3.61). The risk for postpartum hemorrhage requiring blood transfusion was higher (but not statistically significant) in the study group (5.0% vs. 0.0%, aOR 6.43, 95% CI: 0.65-63.24). Patients who chose cesarean delivery during the intrapartum period had a higher (but not statistically significant) composite neonatal morbidity (14.3% vs. 5.7%, aOR 2.24, 95% CI 0.52-9.78) and composite maternal morbidity (28.6% vs.11.8%, aOR 2.90, 95% CI 0.92-9.16) and significantly higher transfusion rate (aOR 16.93, 95% CI 1.53-187.74). CONCLUSION: Cesarean delivery by maternal choice in NTSV patients is not associated with improved neonatal outcomes; in contrast, it is associated with increased composite maternal morbidity and increased transfusion rate.

How did nurses cope with the fast, comprehensive organisational changes at Danish hospital wards during the COVID-19 pandemic? An interview study based on nurses' experiences.

PURPOSE: The COVID-19 pandemic has influenced hospital work and healthcare workers all over the world. We explored how Danish nurses coped with the fast, comprehensive organisational changes in their workplace and identified barriers to and facilitators for organisations ensuring the best possible conditions for nurses to meet these challenges. The study focuses on the organisational setting and how it did or did not support the nurses in their work. METHODS: A qualitative explorative design was used in interviewing 23 nurses who had worked at a COVID-19 ward in one of three hospitals. Data were collected in the summer of 2020, and the analysis was inspired by Paul Ricoeur's theory of narratives and interpretation. RESULTS: The presence of managers in the wards helped the nurses in the form of psychological and practical support. Working within an organisation that provides a safe environment was essential for nurses. The experience of a safe environment allowed nurses to ask questions, which supported them in finding solutions to specific tasks in the new and critical working environment. Barriers to handling the new situation were an absence of managers and a lack of a sense of belongingness and trust. CONCLUSION: This study highlights the need for management to be present in the ward and for organisational support to be available to nurses so they can provide optimal treatment and care when working in new and unknown conditions during a pandemic. Practical assistance from managers to ease the job is beneficial. Furthermore, the presence of management is essential to provide psychological support and create a safe environment because this allows nurses to ask questions about how to better manage new and critical tasks.