Fetal Blood Research Articles

Disease-Modifying Effect of HBS1L-MYB in HbE/β-Thalassemia Patients in Bangladeshi Population

Background: Thalassemias are a group of autosomal recessive disorders and the most common inherited disease worldwide. Fetal hemoglobin (HbF) is the main oxygen carrier protein in the human fetus. Elevated HbF level is known to ameliorate the severity of HbE/β and β-thalassemia. This study aimed to investigate whether two commonly known HbF-associated SNPs (rs28384513 and rs4895441) in the HBS1L-MYB region are associated with HbF level and disease severity in Bangladeshi HbE/β-thalassemia patients. Methods: Blood samples were collected from 160 participants (120 HbE/β-thalassemia patients and 40 healthy controls). Hematological analysis was performed using complete blood count (CBC) and capillary Hb electrophoresis. After genomic DNA extraction, real-time PCR-based high-resolution melting (HRM) for SNP detection, targeting the HBS1L-MYB intergenic region, was done. Results: Patients carrying rs28384513 and rs4895441 SNPs had significantly higher HbF (1.29 ± 1.63 and 1.49 ± 1.7 g/dL, respectively) compared to major allele ‘TT’ and ‘AA’ (0.87 ± 1.1 and 1.19 ± 1.65 g/dL, respectively) with a p-value of 0.01 and 0.03, respectively. It has been detected that HbF levels in SNP-carrying patients significantly correlated with the higher transfusion interval (60 days, r = 0.38, p < 0.0001) and age of first transfusion (65 months, r = 0.26, p < 0.0028) in these patients. Further, non-transfusion-dependent patients had the highest HbF level (2.03 ± 2.05 g/dL) compared to transfusion-dependent moderate (0.58 ± 0.78 g/dL) and severe (0.84 ± 1.27 g/dL) patients generating a significant p-value < 0.0001 in One-Way ANOVA test. The minor allele frequencies of rs28384513 (G) and rs4895441 (G) were found to be 0.43 and 0.11 respectively. Conclusion: These findings suggest that SNPs of HBS1L-MYB may have a role in elevated HbF levels and ameliorating disease severity in terms of transfusion in HbE/β-thalassemia patients.

Microplastic Particles Detected in Fetal Cord Blood, Placenta, and Meconium: A Pilot Study of Nine Mother–Infant Pairs in South China

Microplastics (MPs) are emerging environmental pollutants. Pregnancy and infancy are sensitive windows for environmental exposure. However, few studies have investigated the presence of MPs in mother–infant pairs, or the exposure source. In this study, nine mother–infant pairs were recruited, and samples of placenta, cord blood, and meconium were collected. Information about the living environment and dietary habits were collected to determine the source of exposure during pregnancy. Micro-Raman spectroscopy was applied to identify MPs. In total, 9, 4, and 14 types of MPs were identified in the placenta, cord blood, and meconium samples, with particle counts of 34, 14, and 80, respectively. More than 80.47% of MPs detected in samples had a size of 100–400 μm. The abundance of MPs exhibited the order of meconium > placenta > cord blood (Hc = 14.959, p < 0.01). We found that the abundance of MPs in meconium from women who drank tea ≥ 3 times/week during pregnancy was lower than in those who drank less (p = 0.048). Our study presents evidence of MPs transfer via the placenta–cord blood–meconium pathway. We also found that the habit of drinking tea among pregnant women might be related to the abundance of MPs in meconium.

From old to new: Repurposed drugs in the battle towards curing sickle cell disease.

This commentary discusses the therapeutic potential of drug repurposing in sickle cell disease, highlighting the efficacy of hydroxyurea in enhancing fetal haemoglobin and the work of Raz etal. discussing the potential of using memantine for improving cognitive function, while emphasizing the need for further research. Commentary on: Raz etal. Memantine treatment in sickle cell disease: A 1-year study of its effects on cognitive functions and neural processing. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19866.

Impact of hydroxycarbamide treatment on the whole‐blood transcriptome in sickle cell disease

SummaryHydroxycarbamide (HC) is the most widely used therapeutic for individuals with sickle cell disease (SCD, including sickle cell anemia and other forms of the disease). HC's clinical benefits are primarily associated with its ability to induce foetal haemoglobin (HbF); this limited view of HC's therapeutic potential may lead to its discontinuation when a modest amount of HbF is induced. A better understanding of the HbF‐independent effects of HC on genes and pathways relevant to SCD pathophysiology is therefore needed. In this study, we performed bulk RNA‐Seq on whole blood samples collected from a cohort of 25 paediatric patients with SCD to identify genes and pathways that are affected by treatment with HC. At the maximum tolerated dose (MTD) of HC, patients showed altered expression levels of several genes and biological pathways. Pathways related to haeme metabolism, interferon‐alpha response, and interferon‐gamma response were significantly downregulated at HC MTD relative to the matched pre‐HC samples. Pathways linked with IL2‐STAT5 signalling and TNFα signalling via NF‐Kβ were observed to be up‐regulated at HC MTD. These results illustrate the range of effects exerted by HC during therapy for SCD and pave the way for an improved understanding of the HbF induction‐independent benefits of HC.

Methodology for Biological Sample Collection, Processing, and Storage in the Newcastle 1000 Pregnancy Cohort: Protocol for a Longitudinal, Prospective Population-Based Study in Australia.

Research in the developmental origins of health and disease provides compelling evidence that adverse events during the first 1000 days of life from conception can impact life course health. Despite many decades of research, we still lack a complete understanding of the mechanisms underlying some of these associations. The Newcastle 1000 Study (NEW1000) is a comprehensive, prospective population-based pregnancy cohort study based in Newcastle, New South Wales, Australia, that will recruit pregnant women and their partners at 11-14 weeks' gestation, with assessments at 20, 28, and 36 weeks; birth; 6 weeks; and 6 months, in order to provide detailed data about the first 1000 days of life to investigate the developmental origins of noncommunicable diseases. The study aims to provide a longitudinal multisystem approach to phenotyping, supported by robust clinical data and collection of biological samples in NEW1000. This manuscript describes in detail the large variety of samples collected in the study and the method of collection, storage, and utility of the samples in the biobank, with a particular focus on incorporation of the samples into emerging and novel large-scale "-omics" platforms, including the genome, microbiome, epigenome, transcriptome, fragmentome, metabolome, proteome, exposome, and cell-free DNA and RNA. Specifically, this manuscript details the methods used to collect, process, and store biological samples, including maternal, paternal, and fetal blood, microbiome (stool, skin, vaginal, oral), urine, saliva, hair, toenail, placenta, colostrum, and breastmilk. Recruitment for the study began in March 2021. As of July 2024, 1040 women and 684 partners were enrolled, with 922 infants born. The NEW1000 biobank contains 24,357 plasma aliquots from ethylenediaminetetraacetic acid (EDTA) tubes, 5284 buffy coat aliquots, 4000 plasma aliquots from lithium heparin tubes, 15,884 blood serum aliquots, 2977 PAX RNA tubes, 26,595 urine sample aliquots, 2280 fecal swabs, 17,687 microbiome swabs, 2356 saliva sample aliquots, 1195 breastmilk sample aliquots, 4007 placental tissue aliquots, 2680 hair samples, and 2193 nail samples. NEW1000 will generate a multigenerational, deeply phenotyped cohort with a comprehensive biobank of samples relevant to a large variety of analyses, including multiple -omics platforms. DERR1-10.2196/63562.

Discovery and Optimization of First-in-Class Molecular Glue Degraders of the WIZ Transcription Factor for Fetal Hemoglobin Induction to Treat Sickle Cell Disease.

Sickle cell disease (SCD) is a prevalent, life-threatening condition with few treatment options, attributed to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) with small molecules has been pursued as a treatment to ameliorate many disease complications but with limited success. Herein, we report the discovery of 10, a novel, potent, and selective molecular glue degrader of the transcription factor WIZ that robustly induces HbF expression as a potential treatment for SCD. 10 was optimized from a phenotypic screening hit utilizing insights from X-ray crystallography and computational modeling to improve potency, selectivity and in vivo exposure. In an hNBSGW mouse xenograft model, 10 demonstrated robust WIZ degradation and HbF induction. These results highlight the potential of WIZ degraders as a promising therapy for sickle cell disease.

Fetal hemoglobin in adulthood

Fetal hemoglobin in adulthood

Microalbuminuria in Children With Sickle Cell Disease in the Eastern Province of Saudi Arabia.

Sickle cell disease (SCD) complications, such as sickle cell nephropathy (SCN), may begin in childhood and progress insidiously to chronic kidney disease in adulthood. In Saudi Arabia (SA), there is a lack of studies evaluating kidney function in children with SCD. This study aims to assess microalbuminuria (MA) as an early marker of renal dysfunction in SCD children living in the Eastern region of SA, to potentially institute appropriate early treatment. A prospective cross-sectional study was conducted on 114 Saudi children with SCD under the age of 14 years who attended the pediatric hematology clinic for routine follow-up. Demographic and clinical information were collected from the patients and their parents, who provided informed consent. Morning urine samples were collected and tested for the presence of MA using the urinary albumin/creatinine ratio (ACR). Blood samples were also collected for basic laboratory investigations. The prevalence of MA and its correlation with various clinical and laboratory data were analyzed. Additionally, a comparison of clinical characteristics and MA was conducted between children originating from the Southwestern (SW) and Eastern regions of the country, all of whom lived in the Eastern Province. A total of 114 children with SCD were included in the study. The mean age was 8.8 ± 3.2 years, with a male-to-female ratio of 1.3:1. Based on their region of origin, they were divided into two groups: Eastern (n = 26/114) and SW (n = 88/114). MA was detected in 28 patients (24.6%), with no significant difference in prevalence between the two groups. There was no significant statistical difference in clinical and laboratory data between the groups, except for hemoglobin F (HBF) levels and the use of hydroxyurea (HU). HBF levels were significantly higher in children from the Eastern region, while more SW patients used HU. No correlation was found between MA and any of the studied variables. MA is common in children with SCD in the Eastern region of SA, with no difference in its prevalence between children of the two different ancestries carrying the Arab-Indian (AI) and African haplotypes. It is not associated with any of the studied clinical variables in this report. Further studies are needed to confirm these findings.

Neurodevelopmental Outcomes in Neonates Surviving Fetomaternal Hemorrhage Compared with a Matched Unexposed Group in a Large Integrated Health Care System.

This study aimed to assess short-term neurodevelopmental outcomes for neonates affected by fetomaternal hemorrhage (FMH) and compare them with an unexposed group. A retrospective cohort analysis was conducted within a large integrated medical system spanning from 2008 to 2018. Neurodevelopmental outcomes of neonatal survivors of FMH were compared with matched controls. Clinically significant FMH in survivors was defined by maternal flow cytometry for fetal hemoglobin result of >0.10% and neonatal transfusion requirement. One unexposed infant was identified for each surviving FMH-exposed infant, matched by gestational age at delivery (±1 week), birth year, sex, and race/ethnicity. The primary outcome was a diagnosis of neurodevelopmental impairment, identified using the International Classification of Diseases (ICD), 9th and 10th Revisions (ICD-9 and ICD-10) codes. Results were presented as proportions, means, medians, and interquartile ranges. Comparisons were performed using chi-square and Fisher's exact tests. A Cox proportional hazards regression model was conducted to examine associations between cognitive and developmental outcomes and FMH exposure. Among 137 pregnancies with clinically significant FMH, 80 resulted in intrauterine demise, 57 neonates required blood transfusion, and 4 neonates requiring transfusion demised during birth hospitalization. No significant difference in rates of neurodevelopmental impairment was found between FMH-exposed and unexposed infants (26.4 vs. 24.6%, p = 0.8). Similar findings were observed in preterm (37 vs. 31.6%, p = 0.7) and term neonates (15.4 vs. 14.8%, p = 1.0). Cox regression showed no significant association between neurodevelopmental outcomes and FMH exposure (1.17 [95% CI: 0.61-2.22]; p = 0.6). Despite the significant perinatal morbidity and mortality associated with FMH, surviving infants did not show a significant difference in neurodevelopmental diagnoses compared to matched unexposed infants. However, definitive conclusions are limited due to the rarity of FMH requiring transfusion and the small exposed sample size, warranting further evaluation in a larger cohort. · FMH is associated with profound fetal and neonatal morbidity and mortality.. · Impact on neurologic development for infants surviving FMH is unknown.. · Neurodevelopmental outcomes did not differ between survivors of FMH compared to matched controls..

Clinical burden and healthcare resource utilization associated with managing sickle cell disease with recurrent vaso-occlusive crises in France

Objective This retrospective, real-world claims database analysis described the clinical burden and healthcare resource utilization (HCRU) among patients with sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs) in France. Methods The French National Health Data System database (système national des données de santé) was used to identify eligible patients from 1 January 2012 to 1 March 2019. Inclusion criteria were a SCD diagnosis, ≥2 VOCs/year for ≥2 consecutive years following the diagnosis, and ≥1 year of follow-up data to 1 March 2020. Patients with hereditary persistence of fetal hemoglobin or hematopoietic stem cell transplant in their medical records were excluded. Clinical complications, mortality, treatment use, and HCRU were evaluated during follow-up. Results Overall, 4602 patients with SCD with recurrent VOCs were eligible; their mean (standard deviation [SD]) age was 19.8 (13.5) years, and 51.8% were female. Patients experienced a mean (SD) of 3.82 (3.57) VOCs per patient per year (PPPY). Prevalent complications were anemia or leukocytosis (44.1%), infections (42.0%), and organ failure (38.2%). In total, 101 (2.2%) patients died during follow-up (mean age of death [SD]: 39.3 [17.5] years; mortality rate: 0.64 deaths per 100 person-years). Most patients received opioids (89.1%) and hydroxycarbamide (72.8%). Patients had a mean of 5.7 inpatient hospitalizations, 6.0 emergency room visits, 6.6 outpatient visits, and 13.4 outpatient prescriptions PPPY. Conclusions Patients with SCD with recurrent VOCs in France have substantial clinical complications, mortality, and HCRU despite currently available treatment options. Innovative treatments that reduce frequency of or eliminate VOCs are needed to alleviate the burden associated with SCD.

Fetal Red Blood Cells: A Comprehensive Review of Biological Properties and Implications for Neonatal Transfusion.

Transfusion guidelines worldwide include recommendations regarding the storage length, irradiation, or even donor cytomegalovirus serostatus of red blood cell (RBC) units for anemic neonates. Nevertheless, it is totally overlooked that RBCs of these patients fundamentally differ from those of older children and adults. These differences vary from size, shape, hemoglobin composition, and oxygen transport to membrane characteristics, cellular metabolism, and lifespan. Due to these profound dissimilarities, repeated transfusions of adult RBCs in neonates deeply modify the physiology of circulating RBC populations. Unsurprisingly, the number of RBC transfusions in preterm neonates, particularly if born before 28 weeks of gestation, predicts morbidity and mortality. This review provides a comprehensive description of the biological properties of fetal, cord blood, and neonatal RBCs, including the implications that neonatal RBCs, and their replacement by adult RBCs, may have for perinatal disease pathophysiology.

Identification of small molecule agonists of fetal hemoglobin expression for the treatment of sickle cell disease.

Induction of fetal hemoglobin (HbF) has been shown to be a viable therapeutic approach to treating sickle cell disease and potentially other β-hemoglobinopathies. To identify targets and target-modulating small molecules that enhance HbF expression, we engineered a human umbilical-derived erythroid progenitor reporter cell line (HUDEP2_HBG1_HiBiT) by genetically tagging a HiBiT peptide to the carboxyl (C)-terminus of the endogenous HBG1 gene locus, which codes for γ-globin protein, a component of HbF. Employing this reporter cell line, we performed a chemogenomic screen of approximately 5000 compounds annotated with known targets or mechanisms that have achieved clinical stage or approval by the US Food and Drug Administration (FDA). Among them, 10 compounds were confirmed for their ability to induce HbF in the HUDEP2 cell line. These include several known HbF inducers, such as pomalidomide, lenalidomide, decitabine, idoxuridine, and azacytidine, which validate the translational nature of this screening platform. We identified avadomide, autophinib, triciribine, and R574 as novel HbF inducers from these screens. We orthogonally confirmed HbF induction activities of the top hits in both parental HUDEP2 cells as well as in human primary CD34+ hematopoietic stem and progenitor cells (HSPCs). Further, we demonstrated that pomalidomide and avadomide, but not idoxuridine, induced HbF expression through downregulation of several transcriptional repressors such as BCL11A, ZBTB7A, and IKZF1. These studies demonstrate a robust phenotypic screening workflow that can be applied to large-scale small molecule profiling campaigns for the discovery of targets and pathways, as well as novel therapeutics for sickle cell disease and other β-hemoglobinopathies.

Long-term hypoxia modulates depolarization activation of BKCa currents in fetal sheep middle cerebral arterial myocytes.

Previous evidence indicates that gestational hypoxia disrupts cerebrovascular development, increasing the risk of intracranial hemorrhage and stroke in the newborn. Due to the role of cytosolic Ca2+ in regulating vascular smooth muscle (VSM) tone and fetal cerebrovascular blood flow, understanding Ca2+ signals can offer insight into the pathophysiological disruptions taking place in hypoxia-related perinatal cerebrovascular disease. This study aimed to determine the extent to which gestational hypoxia disrupts local Ca2+ sparks and whole-cell Ca2+ signals and coupling with BKCa channel activity. Confocal imaging of cytosolic Ca2+ and recording BKCa currents of fetal sheep middle cerebral arterial (MCA) myocytes was performed. MCAs were isolated from term fetal sheep (∼140 days of gestation) from ewes held at low- (700 m) and high-altitude (3,801 m) hypoxia (LTH) for 100+ days of gestation. Arteries were depolarized with 30 mM KCl (30K), in the presence or absence of 10 μM ryanodine (Ry), to block RyR mediated Ca2+ release. Membrane depolarization increased Ry-sensitive Ca2+ spark frequency in normoxic and LTH groups along with BKCa activity. LTH reduced Ca2+ spark and whole-cell Ca2+ activity and induced a large leftward shift in the voltage-dependence of BKCa current activation. The influence of LTH on the spatial and temporal aspects of Ca2+ sparks and whole-cell Ca2+ responses varied. Overall, LTH attenuates Ca2+ signaling while increasing the coupling of Ca2+ sparks to BKCa activity; a process that potentially helps maintain oxygen delivery to the developing brain.

A Novel One-Sample Mendelian Randomization Approach for Count-Type Outcomes That Is Robust to Correlated and Uncorrelated Pleiotropic Effects.

We propose two novel one-sample Mendelian randomization (MR) approaches to causal inference from count-type health outcomes, tailored to both equidispersion and overdispersion conditions. Selecting valid single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) poses a key challenge for MR approaches, as it requires meeting the necessary IV assumptions. To bolster the proposed approaches by addressing violations of IV assumptions, we incorporate a process for removing invalid SNPs that violate the assumptions. In simulations, our proposed approaches demonstrate robustness to the violations, delivering valid estimates, and interpretable type-I errors and statistical power. This increases the practical applicability of the models. We applied the proposed approaches to evaluate the causal effect of fetal hemoglobin (HbF) on the vaso-occlusive crisis and acute chest syndrome (ACS) events in patients with sickle cell disease (SCD) and revealed the causal relation between HbF and ACS events in these patients. We also developed a user-friendly Shiny web application to facilitate researchers' exploration of causal relations.

Study protocol for an observational cohort study of heat stress impacts in pregnancy in The Gambia, West Africa

Climate change has resulted in an increase in heat exposure globally. There is strong evidence that this increased heat stress is associated with poor maternal and fetal outcomes, especially in vulnerable populations. However, there remains poor understanding of the biological pathways and mechanisms involved in the impact of heat in pregnancy. This observational cohort study of 764 pregnant participants based in sub-Saharan Africa, a geographical region at risk of extreme heat events, aims to evaluate the physiological and biochemical changes that occur in pregnancy due to heat stress. The key objectives of the study are to 1) map exposure to heat stress in the cohort and understand what environmental, social and community factors increase the risk of extreme heat exposure; 2) assess the impact of heat stress on maternal health, e.g. heat strain, subjective psychological well-being, sleep and activity level; 3) evaluate how heat stress impacts placenta structure and function; 4) determine how chronic heat exposure impacts birth outcomes; and 5) explore the epigenetic changes in the placenta and infant by heat stress exposure per trimester. Pregnant women will be recruited from two distinct regions in The Gambia to exploit the naturally occurring heat gradient across the country. Microclimate mapping of the area of recruitment will give detailed exposure measurements. Participants will be asked to wear a watch-style device at 28- and 35-weeks gestational age to evaluate maternal heart rate, activity and sleep. At the end of the week, an ultrasound scan will be performed to evaluate fetal size and placental blood flow. At delivery, birth outcomes will be recorded and maternal, placental and cord samples taken for epigenetic, biochemical and histological evaluation. Evaluation of neuro-behaviour and final infant samples will be taken at 1 month following birth.

Fructose metabolism is unregulated in cancers and placentae.

Fructose and lactate are present in high concentrations in uterine luminal fluid, fetal fluids and fetal blood of ungulates and cetaceans, but their roles have been ignored and they have been considered waste products of pregnancy. This review provides evidence for key roles of both fructose and lactate in support of key metabolic pathways required for growth and development of fetal-placental tissues, implantation and placentation. The uterus and placenta of ungulates convert glucose to fructose via the polyol pathway. Fructose is sequestered within the uterus and cannot be transported back into the maternal circulation. Fructose is phosphorylated by ketohexokinase to fructose-1-PO4 (F1P) by that is metabolized via the fructolysis pathway to yield dihydoxyacetone phosphate and glyceraldehyde-3-PO4 that are downstream of phosphofructokinase. Thus, there is no inhibition of the fructolysis pathway by low pH, citrate or ATP which allows F1P to continuously generate substrates for the pentose cycle, hexosamine biosynthesis pathway, one-carbon metabolism and tricarboxylic acid cycle, as well as lactate. Lactate sustains the activity of hypoxia-inducible factor alpha and its downstream targets such as vascular endothelial growth factor to increase utero-placental blood flow critical to growth and development of the fetal-placental tissues and a successful outcome of pregnancy. Pregnancy has been referred to as a controlled cancer and this review addresses similarities regarding metabolic aspects of tumors and the placenta.

The Current Role of Hydroxyurea in the Treatment of Sickle Cell Anemia.

Despite advancements in treatment of sickle cell disease (SCD), hydroxyurea, a ribonucleotide reductase inhibitor, remains the cornerstone of therapy. While its primary effect is the elevation of fetal hemoglobin (HbF), hydroxyurea's mechanisms of action are multifaceted. Hydroxyurea (HU) reduces leukocyte and platelet counts, decreases the expression of endothelial adhesion molecules CD36 and CD49d, and increases nitric oxide and cyclic nucleotide levels, which may facilitate vascular dilation and further HbF induction. Numerous studies have demonstrated that hydroxyurea therapy reduces the frequency of painful episodes, acute chest syndrome, and the need for erythrocyte transfusions and hospitalizations. Long-term use of hydroxyurea leads to reduced morbidity and mortality. Hydroxyurea should be initiated in children from 9 months of age, including asymptomatic individuals, and is recommended for adults experiencing pain crises that significantly interfere with daily activities or quality of life, as well as those with severe or recurrent vaso-occlusive crises, ACS, or severe symptomatic anemia. Hydroxyurea is not recommended during pregnancy or lactation due to potential teratogenic effects and transfer into breast milk. However, its use may be considered in high-risk patients, particularly during the second and third trimesters. Concerns about secondary tumor development have not been substantiated in long-term follow-up studies. Alternative therapies, including L-glutamine, crizanlizumab, and voxelotor, are not presently approved or available for clinical use in Europe.

Efficacy and safety of thalidomide in patients with β-thalassemia intermedia and major.

To investigate the short-term and long-term efficacy and safety of thalidomide in the treatment of intermediate and severe β-thalassemia. We analyzed patients with intermediate and severe β-thalassemia treated at our hospital from February 2019 to February 2024. Patients who received treatment for more than 3 months were included. The efficacy of thalidomide was assessed by comparing changes in hemoglobin (Hb), ferritin, bilirubin, and Hb electrophoresis before and after treatment. Adverse drug reactions during treatment were also recorded. A total of 42 β-thalassemia patients were included, with thalidomide dosages ranging from 75 to 150 mg/d. The response rates at 1, 3, and 6 months of treatment were 73.8% (31/42), 75.0% (24/32), and 94.7% (18/19), respectively. The increase in Hb levels was primarily attributed to fetal hemoglobin (HbF). After 1 month of treatment, the HbF percentage increased from a baseline of 34.04 ± 27.58% to 56.25 ± 28.40% (P < .001). At 3 and 6 months, HbF further increased to 67.21 ± 27.12% (P < .001) and 73.93 ± 22.96% (P < .001), respectively. The average duration of thalidomide treatment was 25.3 ± 9.2 months (range: 4-60 months), with 6 patients treated for over 60 months and 18 patients for over 48 months. Two homozygous patients who failed thalidomide treatment achieved Hb levels above 100 g/L and discontinued transfusion therapy after 3 months of hydroxyurea treatment. The most common adverse reaction was somnolence, which was mild and tolerable. Thalidomide demonstrates significant and sustained therapeutic effects in β-thalassemia patients. The adverse reactions are mild and tolerable, allowing patients to continue treatment.

BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations.

An increasing number of individuals with intellectual developmental disorder (IDD) and heterozygous variants in BCL11A are identified, yet our knowledge of manifestations and mutational spectrum is lacking. To address this, we performed detailed analysis of 42 individuals with BCL11A-related IDD (BCL11A-IDD, a.k.a. Dias-Logan syndrome) ascertained through an international collaborative network, and reviewed 35 additional previously reported patients. Analysis of 77 affected individuals identified 60 unique disease-causing variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique BCL11A microdeletions. We define the most prevalent features of BCL11A-IDD: IDD, postnatal-onset microcephaly, hypotonia, behavioral abnormalities, autism spectrum disorder, and persistence of fetal hemoglobin (HbF), and identify autonomic dysregulation as new feature. BCL11A-IDD is distinguished from 2p16 microdeletion syndrome, which has a higher incidence of congenital anomalies. Our results underscore BCL11A as an important transcription factor in human hindbrain development, identifying a previously underrecognized phenotype of a small brainstem with a reduced pons/medulla ratio. Genotype-phenotype correlation revealed an isoform-dependent trend in severity of truncating variants: those affecting all isoforms are associated with higher frequency of hypotonia, and those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S), are associated with higher frequency of postnatal microcephaly. With the largest international cohort to date, this study highlights persistence of fetal hemoglobin as a consistent biomarker and hindbrain abnormalities as a common feature. It contributes significantly to our understanding of BCL11A-IDD through an extensive unbiased multi-center assessment, providing valuable insights for diagnosis, management and counselling, and into BCL11A's role in brain development.

Hemoglobin-oxygen affinity changes in neonatal blood transfusions: RBC selection insights.

Despite preterm newborns often requiring blood transfusions, we have an incomplete understanding of the impact of adult packed red blood cell (pRBC) transfusions on fetal red blood cell (RBC) oxygen affinity. We investigated the influence of adult pRBC on oxygen binding in fetal RBCs obtained from the umbilical cord of preterm newborns. This included exploring the influence of the biological age of adult pRBCs on the oxygen affinity of fetal blood. Cord blood samples from preterm infants were titrated with young (Y-RBC) and old (O-RBC) adult pRBCs using an in vitro transfusion model. Parameters, including oxygen affinity (p50), hemoglobin variants, and red blood cell indices, were measured. The titration of cord blood with adult pRBCs (n = 19) resulted in a concentration-dependent decrease in p50, indicating an increased oxygen affinity. Hemoglobin variant analysis revealed a shift in composition, with a decrease in fetal hemoglobin (HbF) and an increase in adult hemoglobin (HbA) following titration. The impact of biological age was evident, as O-RBCs had a more pronounced effect on p50 values compared to Y-RBCs. Understanding the physiologic implications of transfusing preterm infants with adult pRBCs is important for optimizing transfusion practices in newborns. In an in vitro model, titrating adult pRBC into fetal blood significantly affects oxygen binding Oxygen affinity of fetal blood is significantly increased after titration of adult pRBC. Compared to older RBC subpopulations of adult pRBC, oxygen-binding properties of younger RBC subpopulations of adult pRBC more closely approximate the oxygen affinity of fetal blood. This work highlights the importance of investigating the influence of adult pRBC transfusion on fetal RBC oxygen binding. This may have implications for morbidities in the newborn period related to oxygen physiology.