Fetal Blood Research Articles

Does high body mass index (>25 kg/m2) or weight (>80 kg) reduce the effectiveness of anti-D prophylaxis in Rh(D)-negative pregnant women? A systematic review and meta-analysis.

Haemolytic disease of the foetus and newborn (HDFN) occurs when maternal antibodies, often triggered by foetal antigens, destroy foetal and neonatal red blood cells. Factors like antibody strength, quantity and gestational age influence HDFN severity. Routine antenatal anti-D prophylaxis (RAADP) has significantly reduced HDFN cases. However, the effect of overweight/obesity (body mass index [BMI] > 25/30 kg/m2) on anti-D prophylaxis efficacy remains unclear. This systematic review will examine the impact of BMI on anti D prophylaxis effectiveness in Rh(D) negative pregnant women. We conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) protocols. We searched databases from 1996 to 2023, focusing on studies exploring the link between high BMI/weight and anti-D serum levels in Rh(D)-negative pregnant women with Rh(D)-positive foetuses. Ten eligible studies were included, three suitable for meta-analysis. Study quality was assessed using the Strengthening the Reporting Observation Studies in Epidemiology (STROBE) checklist. Statistical analyses included Pearson correlation coefficients and risk differences. Our meta-analysis revealed a significant negative correlation (r = -0.59, 95% confidence interval [CI]: -0.83 to -0.35, p = 0.007) between high BMI/weight and serial anti-D levels in in Rh(D)-negative pregnant women with Rh(D)-positive foetuses. High BMI/weight had lower odds of serial anti-D level exceeding 30 ng/mL (arcsine risk difference [ARD] = 0.376, 95% CI: 0.143-0.610, p = 0.002). Heterogeneity among studies was low (I2 = 0). While our analysis suggests a potential linkage between high BMI/weight and reduced efficacy of anti-D prophylaxis, caution is warranted due to study limitations. Variability in study design and confounding factors necessitate careful interpretation. Further research is needed to confirm these findings and refine clinical recommendations.

Hemoglobin Electrophoresis versus Kleihauer-Betke to Determine Bone Marrow Suppression in Fetuses Undergoing Intrauterine Transfusion.

Mainstay therapy for fetuses affected by maternal red cell alloimmunization is serial intrauterine transfusion (IUT). Testing to determine when fetal red cells have been replaced with donor cells historically involves the use of the Kleihauer-Betke (KB) test. Hemoglobin (Hgb) electrophoresis testing may be more rapid with a reduced cost of analysis. We aimed to determine the correlation between fetal Hgb electrophoresis versus the traditional KB test. This is a retrospective analysis of all alloimmunized singleton pregnancies undergoing IUT between January 1, 2021, and July 1, 2023. Maternal and fetal characteristics were collected along with the indication for IUT. A final fetal blood sample was obtained at the conclusion of each transfusion and sent for KB testing and Hgb electrophoresis. The primary outcome was the assessment of these parameters in their ability to predict the replacement of the fetal circulating red cell population with donor cells. Linear regression analysis and repeated measures analysis of variance were performed, and p-values less than 0.05 were considered significant. A total of 56 IUTs were performed in 16 patients. There were 39 (69.6%) final KB test values collected and compared with 30 (53.6%) final Hgb electrophoresis values. Hgb electrophoresis when compared with the KB test demonstrated a significant correlation (R 2 = 0.93; 95% confidence interval, 0.61-0.76; p < 0.001). This same finding held true when examining the correlation at each individual IUT as well. The final KB test and Hgb electrophoresis values significantly decreased with each transfusion (p = 0.003). A predominance of adult donor blood was noted by the third transfusion for both laboratory indices. Fetal Hgb electrophoresis obtained at the time of IUT demonstrates a significant correlation with the traditional KB test. · Fetal Hgb electrophoresis following IUT is underexplored. · Hgb electrophoresis is an automated evaluation. · The traditional KB test is a manual evaluation. · These two tests demonstrate significant correlation.

Fetal hemoglobin induction in azacytidine responders enlightens methylation patterns related to blast clearance in higher-risk MDS and CMML

BackgroundAs new treatment options for patients with higher-risk myelodysplastic syndromes are emerging, identification of prognostic markers for hypomethylating agent (HMA) treatment and understanding mechanisms of their delayed and short-term responses are essential. Early fetal hemoglobin (HbF) induction has been suggested as a prognostic indicator for decitabine-treated patients. Although epigenetic mechanisms are assumed, responding patients’ epigenomes have not been thoroughly examined. We aimed to clarify HbF kinetics and prognostic value for azacytidine treated patients, as well as the epigenetic landscape that might influence HbF re-expression and its clinical relevance.ResultsSerial HbF measurements by high-performance liquid chromatography (n = 20) showed induction of HbF only among responders (p = 0.030). Moreover, HbF increase immediately after the first azacytidine cycle demonstrated prognostic value for progression-free survival (PFS) (p = 0.032, HR = 0.19, CI 0.24–1.63). Changes in methylation patterns were revealed with methylated DNA genome-wide sequencing analysis (n = 7) for FOG-1, RCOR-1, ZBTB7A and genes of the NuRD-complex components. Targeted pyrosequencing methodology (n = 28) revealed a strong inverse correlation between the degree of γ-globin gene (HBG2) promoter methylation and baseline HbF levels (p = 0.003, rs = − 0.663). A potential epigenetic mechanism of HbF re-expression in azacytidine responders was enlightened by targeted methylation analysis, through hypomethylation of site -53 of HBG2 promoter (p = 0.039, rs = − 0.504), which corresponds to MBD2-NuRD binding site, and to hypermethylation of the CpG326 island of ZBTB7A (p = 0.05, rs = 0.482), a known HbF repressor. These changes were associated to blast cell clearance (pHBG2 = 0.011, rs = 0.480/pZBTB7A = 0.026, rs = 0.427) and showed prognostic value for PFS (pZBTB7A = 0.037, HR = 1.14, CI 0.34–3.8).ConclusionsEarly HbF induction is featured as an accessible prognostic indicator for HMA treatment and the proposed potential epigenetic mechanism of HbF re-expression in azacytidine responders includes hypomethylation of the γ-globin gene promoter region and hypermethylation of the CpG326 island of ZBTB7A. The association of these methylation patterns with blast clearance and their prognostic value for PFS paves the way to discuss in-depth azacytidine epigenetic mechanism of action.Graphical abstract

Genotyping the BCL11A Single Nucleotide Polymorphism and Associated Levels of Fetal Hemoglobin in Mauritanian Sickle Cell Patients.

Sickle cell disease (SCD) is a major heritable genetic disease in sub-Saharan Africa, including Mauritania. Fetal hemoglobin (HbF) can affect the pathophysiology, moderate the clinical course, and offer prospects for curative treatment of SCD. This study aimed to investigate the influence of single nucleotide polymorphisms (SNPs) in the BCL11A gene on the levels of HbF and hematological parameters in Mauritanian sickle cell (HbSS) patients. Complete blood count was assessed in 565 patients suspected to have SCD. Polymerase chain reaction (PCR)-restriction fragment length polymorphism was performed to identify the HbSS, and sequencing was used for genotyping three SNPs: rs4671393 (A>G) and rs11886868 (C>T) in the intron 2 and rs1052520 (G>A) in the 3'UTR regions of the BCL11A gene in 50 sickle cell patients. The prevalence of HbSS among the study population was 8.8% (50/565), and the mean (± standard deviation) of HbF level was 15.0% (± 6.0%). Sequencing showed the presence of three genotypes: AA (13.6%), AG (46.6%), GG (39.6%) in rs4671393; CC (17.6%), CT (48.7%), and TT (33.6%) in rs11886868. All samples from HbSS individuals displayed a wild-type genotype in the rs1052520 allele. The prevalence of minor alleles A (rs4671393) and C (rs11886868) were 37% and 39%, respectively. There was a statistically significant association (p = 0.034) between rs4671393 SNP and elevated HbF (mean 12.72 ± 6.26%). The study of three SNPs in the BCL11A locus in Mauritanian patients with SCD showed a significant association of rs4671393 allele with the HbF level. Further research is needed to explore additional SNPs in the BCL11A locus and investigate other genetic markers reported to modulate HbF levels, such as HBS1L-MYB and Xmn1-HBG2, to improve the management of this potentially life-threatening condition in Mauritania.

The Effect of Preoperative Carbohydrate-containing Fluid Consumption on Maternal Oxidative Stress Markers During Elective Cesarean Delivery

PurposeThe purpose of this study was to evaluate the effect of carbohydrate loading prior to the cesarean surgery under spinal anesthesia on thiols and ischemia-modified albumin (IMA) levels. DesignProspective, randomized placebo-controlled study. MethodsSeventy-nine pregnant women planned for cesarean sections under spinal anesthesia at Karaman Training and Research Hospital were randomized into a control group (group C) (n = 42), and an oral carbohydrate preloading group (group OCH) (n = 37). OCH loading requires consuming 400 mL the night before surgery and 200 mL up to 2 hours before anesthesia. Group OCH consumed an oral carbohydrate-rich beverage (Nutricia-Fantomalt), and group C consumed an equal volume of water. This study investigated thiol-disulfide homeostasis after preoperative carbohydrate consumption. Preoperative gastric fluid, volume, antral cross-sectional area, hypotension following the birth, and fetal blood gas parameters were compared across groups. FindingsThiols and IMA levels did not differ across groups before and after surgery (P > .05). Gastric ultrasonography showed similar antral cross-sectional area and stomach volume between groups (P = .172, P = .128, respectively). When surgery caused hypotension, group OCH received more ephedrine for surgery-induced hypotension, although this difference is not statistically significant (P = .704). A clustered error bar (95% confidence interval) plot with an interpolation line was used for a time-based comparison of mean differences in heart rate and mean arterial pressure between the groups. ConclusionsThis study supports that mothers' thiols and IMA levels were unaffected by preoperative OCH loading before cesarean surgery. We did not examine thiol and its derivatives in umbilical cord blood; hence, we can not comment on thiol/disulfide homeostasis levels in neonates.

Research progress on the effects of exposure to major persistent organic pollutants during pregnancy on the functional development of nervous system in children

Persistent Organic Pollutants (POPs) have the characteristics of resistance to environmental degradation, bioaccumulation and long-distance migration potential. Maternal exposure to POPs during pregnancy can enter the fetal blood circulation through the placental barrier, and have a potential impact on the functional development of the nervous system of the offspring. This in turn leads to the occurrence and development of neurological defects and diseases in adulthood. The purpose of this paper is to elucidate the effects of exposure to three major POPs (organochlorine compounds, perfluoroalkyl and polyfluoroalkyl substances, and polybrominated diphenyl ethers) during pregnancy on the functional development of the nervous system (social emotions, cognition, language, exercise, and adaptability) in children, and to provide reference for subsequent studies.

MYCT1 controls environmental sensing in human haematopoietic stem cells

The processes that govern human haematopoietic stem cell (HSC) self-renewal and engraftment are poorly understood and challenging to recapitulate in culture to reliably expand functional HSCs1–3. Here we identify MYC target 1 (MYCT1; also known as MTLC) as a crucial human HSC regulator that moderates endocytosis and environmental sensing in HSCs. MYCT1 is selectively expressed in undifferentiated human haematopoietic stem and progenitor cells (HSPCs) and endothelial cells but becomes markedly downregulated during HSC culture. Lentivirus-mediated knockdown of MYCT1 prevented human fetal liver and cord blood (CB) HSPC expansion and engraftment. By contrast, restoring MYCT1 expression improved the expansion and engraftment of cultured CB HSPCs. Single-cell RNA sequencing of human CB HSPCs in which MYCT1 was knocked down or overexpressed revealed that MYCT1 governs important regulatory programmes and cellular properties essential for HSC stemness, such as ETS factor expression and low mitochondrial activity. MYCT1 is localized in the endosomal membrane in HSPCs and interacts with vesicle trafficking regulators and signalling machinery. MYCT1 loss in HSPCs led to excessive endocytosis and hyperactive signalling responses, whereas restoring MYCT1 expression balanced culture-induced endocytosis and dysregulated signalling. Moreover, sorting cultured CB HSPCs on the basis of lowest endocytosis rate identified HSPCs with preserved MYCT1 expression and MYCT1-regulated HSC stemness programmes. Our work identifies MYCT1-moderated endocytosis and environmental sensing as essential regulatory mechanisms required to preserve human HSC stemness. Our data also pinpoint silencing of MYCT1 as a cell-culture-induced vulnerability that compromises human HSC expansion.

The Discovery of Selective Protein Arginine Methyltransferase 5 Inhibitors in the Management of β-Thalassemia through Computational Methods.

β-Thalassemia is an inherited genetic disorder associated with β-globin chain synthesis, which ultimately becomes anemia. Adenosine-2,3-dialdehyde, by inhibiting arginine methyl transferase 5 (PRMT5), can induce fetal hemoglobin (HbF) levels. Hence, the materialization of PRMT5 inhibitors is considered a promising therapy in the management of β-thalassemia. This study conducted a virtual screening of certain compounds similar to 5'-deoxy-5'methyladenosine (3XV) using the PubChem database. The top 10 compounds were chosen based on the best docking scores, while their interactions with the PRMT5 active site were analyzed. Further, the top two compounds demonstrating the lowest binding energy were subjected to drug-likeness analysis and pharmacokinetic property predictions, followed by molecular dynamics simulation studies. Based on the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) score and molecular interactions, (3R,4S)-2-(6-aminopurin-9-yl)-5-[(4-ethylcyclohexyl)sulfanylmethyl]oxolane-3,4-diol (TOP1) and 2-(6-Aminopurin-9-yl)-5-[(6-aminopurin-9-yl)methylsulfanylmethyl]oxolane-3,4-diol (TOP2) were identified as potential hit compounds, while TOP1 exhibited higher binding affinity and stabler binding capabilities than TOP2 during molecular dynamics simulation (MDS) analysis. Taken together, the outcomes of our study could aid researchers in identifying promising PRMT5 inhibitors. Moreover, further investigations through in vivo and in vitro experiments would unquestionably confirm that this compound could be employed as a therapeutic drug in the management of β-thalassemia.

Reviewing the impact of hydroxyurea on DNA methylation and its potential clinical implications in sickle cell disease.

Hydroxyurea (HU) is the most common drug therapy for sickle cell disease (SCD). The clinical benefits of HU derive from its upregulation of fetal hemoglobin (HbF), which reduces aggregation of the mutated sickle hemoglobin protein (HbS) and reduces SCD symptoms and complications. However, some individuals do not respond to HU, or stop responding over time. Unfortunately, current understanding of the mechanism of action of HU is limited, hindering the ability of clinicians to identify those patients who will respond to HU and to optimize treatment for those receiving HU. Given that epigenetic modifications are essential to erythropoiesis and HbF expression, we hypothesize that some effects of HU may be mediated by epigenetic modifications, specifically DNA methylation. However, few studies have investigated this possibility and the effects of HU on DNA methylation remain relatively understudied. In this review, we discuss the evidence linking HU treatment to DNA methylation changes and associated gene expression changes, with an emphasis on studies that were performed in individuals with SCD. Overall, although HU can affect DNA methylation, research on these changes and their clinical effects remains limited. Further study is likely to contribute to our understanding of hematopoiesis and benefit patients suffering from SCD.

Point-of-care Diagnostic for Foetal Haemoglobin in Kids for Sickle Cell Disease in Ghana

Point-of-care Diagnostic for Foetal Haemoglobin in Kids for Sickle Cell Disease in Ghana

Ephedrine Infusion Prevents Hypotension and Reduces Nausea in Cesarean Section Under Spinal Anesthesia

In this study, we aimed to evaluate the efficacy of ephedrine infusion in preventing hypotension and minimizing nausea in healthy pregnant women undergoing elective cesarean sections with spinal anesthesia. Forty-four participants were included, with 20 receiving ephedrine infusion and 24 serving as controls receiving bolus injections. Results revealed a significant reduction in the incidence of hypotension (p &gt; 0.1) and nausea (p &lt; 0.001) in the infusion group compared to the controls. No instances of reactive hypertension were observed in the infusion group. Other variables including Apgar scores, fetal blood gas tensions, and onset of respiration remained comparable between the groups. These findings suggest that ephedrine infusion is not only safe but also preferable in mitigating adverse events during cesarean sections under spinal anesthesia in normal pregnancies. Highlights: Ephedrine infusion effectively prevents hypotension during cesarean sections under spinal anesthesia. Administration of ephedrine infusion significantly reduces the incidence of nausea compared to bolus injections. No instances of reactive hypertension were observed in patients receiving ephedrine infusion, highlighting its safety profile in this context. Keywords: Ephedrine Infusion, Cesarean Section, Spinal Anesthesia, Hypotension Prevention, Nausea Reduction

Novel biomarkers of preterm brain injury from blood transcriptome in sheep model of intrauterine asphyxia.

Infants born preterm have a higher incidence of neurological deficits. A key step in finding effective treatments is to identify biomarkers that reliably predict outcome. Following umbilical cord occlusion (UCO) in pregnant sheep, whole fetal blood RNA was sequenced pre- and post-UCO, brain injury outcome was determined by battery of neuropathology scoring and the transcriptome signature correlated to the degree of brain injury. Additionally, we developed a novel analytical procedure to deduce cell blood composition over time. Sixty-one genes were identified with significant altered expression after UCO. In pre-UCO blood, the level of three mRNAs (Trex2, Znf280b, novel miRNA) and in post-UCO, four mRNAs (Fam184a, Angptl2, novel lincRNA and an unknown protein-coding gene) were associated to brain injury (FDR < 0.01). Several of these mRNAs are related to inflammation and angiogenesis. Pathway analysis highlighted genes playing a role in perinatal death and growth failure. Results also indicate that several leukocyte populations undergo significant changes after UCO. We have used a whole transcriptomic approach to uncover novel biomarkers in fetal blood that correlate to neuropathology in the preterm sheep brain. The current data forms a basis for future studies to investigate mechanisms of these mRNAs in the injury progression. Trend analysis of genes following asphyxia reveal a group of genes associated with perinatal death and growth failure. Several pre-asphyxia transcripts were associated to brain injury severity suggesting genomic susceptibility to injury. Several post-asphyxia transcripts were correlated to brain injury severity, thus, serve as potential novel biomarkers of injury outcome. Successfully adaptation of cell profiling algorithms suggests significant changes in blood cell composition following asphyxia.

Fetal growth delay caused by loss of non-canonical imprinting is resolved late in pregnancy and culminates in offspring overgrowth.

Germline epigenetic programming, including genomic imprinting, substantially influences offspring development. Polycomb Repressive Complex 2 (PRC2) plays an important role in Histone 3 Lysine 27 trimethylation (H3K27me3)-dependent imprinting, loss of which leads to growth and developmental changes in mouse offspring. In this study, we show that offspring from mouse oocytes lacking the PRC2 protein Embryonic Ectoderm Development (EED) were initially developmentally delayed, characterised by low blastocyst cell counts and substantial growth delay in mid-gestation embryos. This initial developmental delay was resolved as offspring underwent accelerated fetal development and growth in late gestation resulting in offspring that were similar stage and weight to controls at birth. The accelerated development and growth in offspring from Eed-null oocytes was associated with remodelling of the placenta, which involved an increase in fetal and maternal tissue size, conspicuous expansion of the glycogen-enriched cell population, and delayed parturition. Despite placental remodelling and accelerated offspring fetal growth and development, placental efficiency, and fetal blood glucose levels were low, and the fetal blood metabolome was unchanged. Moreover, while expression of the H3K27me3-imprinted gene and amino acid transporter Slc38a4 was increased, fetal blood levels of individual amino acids were similar to controls, indicating that placental amino acid transport was not enhanced. Genome-wide analyses identified extensive transcriptional dysregulation and DNA methylation changes in affected placentas, including a range of imprinted and non-imprinted genes. Together, while deletion of Eed in growing oocytes resulted in fetal growth and developmental delay and placental hyperplasia, our data indicate a remarkable capacity for offspring fetal growth to be normalised despite inefficient placental function and the loss of H3K27me3-dependent genomic imprinting.

Bovine papillomavirus vertical transmission: BPV diversity and expression in maternal and fetal tissues.

Bovine Papillomaviruses (BPVs) constitute a diverse group within the Papillomaviridae family, playing a crucial role in bovine health and economic considerations. This study investigates the dynamics of vertical transmission of BPV in cattle, focusing on five cows and their reproductive tissues, as well as three gravid cows and their fetuses. DNA and RNA samples were extracted from the warts, fetal skin, placenta, uterus, ovary, and blood of cows, as well as the skin and blood of fetuses. Polymerase Chain Reaction (PCR) targeted BPV types 1-6 and 8-14, was assessed in both cows and fetuses. Additionally, Reverse Transcription PCR (RT-PCR) examined BPV-2 E5 oncogene expression in the skin and reproductive sites of mother cows and fetuses. Our findings unveil a rich diversity of BPV types, including BPV-2, 3, 9, 10, 12, and 14, present in both maternal and fetal tissues. Intriguingly, certain types, namely BPV-4, 6, 8, and 11, were exclusively identified in maternal tissues A higher diversity of BPVs was observed in cow warts, followed by cow blood, fetal blood, and fetal skin. Strikingly similar BPV types in gravid cow blood and fetuses suggest primary dissemination through the bloodstream and transmission via the placenta, though detected in lower numbers in cow uterus and ovary. Histopathological analysis revealed no abnormalities in the reproductive tissues despite the presence of BPV. However, in one bladder sample from a cow that did not consume bracken fern, urothelial neoplasia in situ was observed. The study extends beyond detection, exploring the expression of the BPV-2 E5 oncogene in fetal tissues, providing insights into potential cell implications. Comparative analyses with previous studies highlight the uniqueness of our investigation, encompassing a broader array of BPV types in the gravid cows and their fetuses. The findings not only establish a foundation for further investigations into the mechanisms of vertical transmission but also highlight the need for targeted interventions and surveillance strategies to mitigate potential health risks associated with specific BPV types.

Interference of hemoglobin variants with HbA1c measurements by six commonly used HbA1c methods.

Glycated hemoglobin, or hemoglobin A1c (HbA1c), serves as a crucial marker for diagnosing diabetes and monitoring its progression. We aimed to assess the interference posed by common Hb variants on popular HbA1c measurement systems. A total of 63 variant and nonvariant samples with target values assigned by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC)-calibrated methods were included. We assessed 6 methods for measuring HbA1c in the presence of HbS, HbC, HbD, HbE, and fetal hemoglobin (HbF): 2 cation-exchange high-performance liquid chromatography (HPLC) methods (Bio-Rad D-100 and HLC-723 G8), a capillary electrophoresis (CE) method (Sebia Capillarys 3 TERA), an immunoassay (Roche c501), an enzyme assay system (Mindray BS-600M), and a boronate affinity method (Primus Premier Hb9210). The HbA1c results for nonvariant samples from the 6 methods were in good agreement with the IFCC-calibrated method results. The Bio-Rad D-100, Capillarys 3, Mindray BS-600M, Premier Hb9210, and Roche c501 showed no interference from HbS, HbC, HbD, and HbE. Clinically significant interference was observed for the HLC-723 G8 standard mode. Elevated HbF levels caused significant negative biases for all 6 methods, which increased with increasing HbF concentration. Elevated levels of HbF can severely affect HbA1c measurements by borate affinity, immunoassays, and enzyme assays.

Therapeutic Relevance of Inducing Autophagy in β-Thalassemia.

The β-thalassemias are inherited genetic disorders affecting the hematopoietic system. In β-thalassemias, more than 350 mutations of the adult β-globin gene cause the low or absent production of adult hemoglobin (HbA). A clinical parameter affecting the physiology of erythroid cells is the excess of free α-globin. Possible experimental strategies for a reduction in excess free α-globin chains in β-thalassemia are CRISPR-Cas9-based genome editing of the β-globin gene, forcing "de novo" HbA production and fetal hemoglobin (HbF) induction. In addition, a reduction in excess free α-globin chains in β-thalassemia can be achieved by induction of the autophagic process. This process is regulated by the Unc-51-like kinase 1 (Ulk1) gene. The interplay with the PI3K/Akt/TOR pathway, with the activity of the α-globin stabilizing protein (AHSP) and the involvement of microRNAs in autophagy and Ulk1 gene expression, is presented and discussed in the context of identifying novel biomarkers and potential therapeutic targets for β-thalassemia.

Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells.

Therapeutic genome editing of haematopoietic stem cells (HSCs) would provide long-lasting treatments for multiple diseases. However, the in vivo delivery of genetic medicines to HSCs remains challenging, especially in diseased and malignant settings. Here we report on a series of bone-marrow-homing lipid nanoparticles that deliver mRNA to a broad group of at least 14 unique cell types in the bone marrow, including healthy and diseased HSCs, leukaemic stem cells, B cells, T cells, macrophages and leukaemia cells. CRISPR/Cas and base editing is achieved in a mouse model expressing human sickle cell disease phenotypes for potential foetal haemoglobin reactivation and conversion from sickle to non-sickle alleles. Bone-marrow-homing lipid nanoparticles were also able to achieve Cre-recombinase-mediated genetic deletion in bone-marrow-engrafted leukaemic stem cells and leukaemia cells. We show evidence that diverse cell types in the bone marrow niche can be edited using bone-marrow-homing lipid nanoparticles.

Vasa Previa and the Role of Fetal Fibronectin and Cervical Length Surveillance: A Review.

Vasa previa is a pregnancy complication that occurs when unprotected fetal blood vessels traverse the cervical os, placing the fetus at high risk of exsanguination and fetal death. These fetal vessels may be compromised by fetal movement and compression, leading to poor oxygen distribution and asphyxiation. Diagnostic tools for vasa previa management and preterm labor (PTL) include transvaginal ultrasound, cervical length (CL) surveillance and use of fetal fibronectin (FFN) testing. These tools can prove to be quite useful as they allow for lead time in the prediction of PTL and spontaneous rupture of membranes which can result in devastating outcomes for pregnancies affected by vasa previa. We conducted a literature review on vasa previa management and the usefulness of FFN and CL surveillance in predicting PTL and found 36 related papers. Although there is limited research available to show the impact of FFN and CL surveillance in the management of vasa previa, there is sufficient evidence to support FFN and CL surveillance in predicting the onset of PTL, which can have devastating consequences for the pregnancies affected. It can be extrapolated that these tools, by helping to determine pregnancies at risk for PTL, could improve management and outcomes in patients with vasa previa. Future studies investigating the management of vasa previa with FFN and CL surveillance to reduce the burden of PTL and its associated comorbidities are warranted.

Genetic analysis of a fetus with cryptophthalmos due to variants of FREM2 gene

To explore the genetic etiology of a fetus with cryptophthalmos detected by prenatal ultrasonography. A fetus undergoing induced labor at 32nd gestational week due to absence of bilateral eye fissures detected by prenatal ultrasonography in January 2017 was selected as the study subject. Umbilical cord blood sample from the fetus and peripheral blood samples from its parents were collected for the extraction of genomic DNA. Pathogenic variants were screened through whole exome sequencing (WES) and verified by Sanger sequencing. Pathogenicity of candidate variants was verified by bioinformatic analysis and protein structure simulation. Based on the results of genetic testing, prenatal diagnosis was provided to the couple upon their subsequent pregnancy. The couple had four adverse pregnancies previously. The aborted fetus was the fifth, with fused bilateral upper and lower eyelids, poorly developed eyeballs, adhesion of the cornea with the upper eyelid, low-set ears, and abnormal plantar creases, and was diagnosed with cryptophthalmos. WES and Sanger sequencing revealed that the fetus has harbored compound heterozygous variants of the FREM2 gene, namely c.4537G>A (p.D1513N) and c.7292C>T (p.T2431M). Both variants were unreported associated with cryptophthalmos previously. Protein structure simulation showed that they may lead to loss of hydrogen bonds in the protein product. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PM1_Supporting+PM2_Supporting+PM5+PP3+PP4; PM2_Supporting+PM3+PP3+PP4). The mother was performed prenatal diagnosis in her sixth pregnancy based on the variants detected in this family, and delivered a daughter with normal phenotype. The FREM2: c.4537G>A and c.7292C>T compound heterozygous variants probably underlay the pathogenesis of cryptophthalmos in this fetus. Above finding has enriched the mutational spectrum of the FREM2 gene.

Prenatal phenotype and genetic analysis of a fetus with Fibrochondrogenesis 1 due to compound heterozygous variants of COL11A1 gene

To explore the genetic etiology of a fetus with short limbs identified by prenatal ultrasonography. A fetus detected with short limb malformations at Shengjing Hospital Affiliated to China Medical University on October 25, 2021 was selected as the study subject. Prenatal ultrasound and post-abortion imaging were carried out to determine the phenotypic characteristics of the fetus. Amniotic fluid sample of the fetus and peripheral blood samples of its parents were collected. Following extraction of genomic DNA, whole-exome sequencing was carried out. Candidate variants were verified by Sanger sequencing. Online software was used to predict the structural changes of the mutant proteins. Prenatal ultrasound showed that the fetus had a small bell-shaped thorax, markedly shortened limbs, flat midface, a small nose with anteriorly tilted nostrils, and a small mandible. Post-abortion CT showed typical short and wide fetal ribs, cupped metaphyses at both ends, short long bones with wide metaphyses, resulting in a dumbbell-shaped appearance and curved thoracic vertebrae. Whole-exome sequencing revealed that the fetus had harbored compound heterozygous variants of the COL11A1 gene, namely c.2251G>T and c.3790G>T, both of which were predicted to alter the important Gly-X-Y structure of collagen protein. Sanger sequencing confirmed that the variants were respectively inherited from its parents. A rare fetus with Fibrochondrogenesis type 1 due to compound heterozygous variants of the COL11A1 gene has been diagnosed. Above finding has enabled genetic counseling and reproductive guidance for this family.