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BACKGROUND AND AIM: Pervasive disparities characterize sickle cell disease (SCD) care, including limited access to SCD specialists. Rapid deployment of remote healthcare provision and support during the COVID-19 pandemic provides an opportunity to understand telehealth barriers/facilitators for SCD. We aimed to evaluate telehealth experiences and satisfaction for routine visits among adults and caregivers of children with SCD within a US regional collaborative. METHODS: 151 adults ≥ 18 [median (IQR) = 36 (28, 43) years], and 94 caregivers [median child age (IQR) = 12 (7, 14) years] completed a 30-item online survey in 2021 assessing systems issues such as reliable Internet; health information sharing; and consumer focus (e.g., visit started on time). A multivariable logistic regression model was used to evaluate relations between independent variables and the outcome overall satisfaction with telehealth. RESULTS: Patients were primarily diagnosed with sickle cell anemia (60.8%) and prescribed hydroxyurea (57.6%). Satisfaction with telehealth was high (> 90%), but 60.6% of caregivers gave the highest rating compared with 44.9% of adults (p = 0.02). Few accessibility/technical issues were cited, however, caregivers reported more often having home support for telehealth (80.9% vs. 63.6%, p = 0.003). In multivariable analyses, participants seen in large centers (> 200) were more likely to give the highest satisfaction ratings compared with those in smaller centers (

Recombinant adeno-associated viruses (rAAV) are promising for applications in many genome editing techniques through their effectiveness as carriers of DNA homologous donors into primary hematopoietic stem and progenitor cells (HSPCs), but they have many outstanding concerns. Specifically, their biomanufacturing and the variety of factors that influence the quality and consistency of rAAV preps are in question. During the process of rAAV packaging, a cell line is transfected with several DNA plasmids that collectively encode all the necessary information to allow for viral packaging. Ideally, this process results in the packaging of complete viral particles only containing rAAV genomes; however, this is not the case. Through this study, we were able to leverage single-stranded virus (SSV) sequencing, a next-generation sequencing-based method to quantify all DNA species present within rAAV preps. From this, it was determined that much of the DNA within some rAAV preps is not vector-genome derived, and there is wide variability in the contamination by DNA across various preps. Furthermore, we demonstrate that transducing CD34+ HSPCs with preps with higher contaminating DNA resulted in decreased clonogenic potential, altered transcriptomic profiles, and decreased genomic editing. Collectively, this study characterized the effects of DNA contamination within rAAV preps on CD34+ HSPC cellular potential.

Nineteen genetic therapies have been approved by the U.S. Food and Drug Administration (FDA) to date, a number that now includes the first CRISPR genome editing therapy for sickle cell disease, CASGEVY (exagamglogene autotemcel). This extraordinary milestone is widely celebrated because of the promise for future genome editing treatments of previously intractable genetic disorders and cancers. At the same time, such genetic therapies are the most expensive drugs on the market, with list prices exceeding $4 million per patient. Although all approved cell and gene therapies trace their origins to academic or government research institutions, reliance on for-profit pharmaceutical companies for subsequent development and commercialization results in prices that prioritize recouping investments, paying for candidate product failures, and meeting investor and shareholder expectations. To increase affordability and access, sustainable discovery-to-market alternatives are needed that address system-wide deficiencies. Here, we present recommendations of a multi-disciplinary task force assembled to chart such a path. We describe a pricing structure that, once implemented, could reduce per-patient cost tenfold and propose a business model that distributes responsibilities while leveraging diverse funding sources. We also outline how academic licensing provisions, manufacturing innovation and supportive regulations can reduce cost and enable broader patient treatment.

A major limitation of gene therapy for sickle cell disease (SCD) is the availability and access to a potentially curative one-time treatment, due to high treatment costs. We have developed a high-titer bifunctional lentiviral vector (LVV) in a vector backbone that has reduced size, high vector yields, and efficient gene transfer to human CD34+ hematopoietic stem and progenitor cells (HSPCs). This LVV contains locus control region cores expressing an anti-sickling βAS3-globin gene and two microRNA-adapted short hairpin RNA simultaneously targeting BCL11A and ZNF410 transcripts to maximally induce fetal hemoglobin (HbF) expression. This LVV induces high levels of anti-sickling hemoglobins (HbAAS3 + HbF), while concurrently decreasing sickle hemoglobin (HbS). The decrease in HbS and increased anti-sickling hemoglobin impedes deoxygenated HbS polymerization and red blood cell sickling at low vector copy per cell in transduced SCD patient CD34+ cells differentiated into erythrocytes. The dual alterations in red cell hemoglobins ameliorated the SCD phenotype in the SCD Berkeley mouse model in vivo. With high titer and enhanced transduction of HSPC at a low multiplicity of infection, this LVV will increase the number of patient doses of vector from production lots to decrease costs and help improve accessibility to gene therapy for SCD.

AimTo develop a non-invasive prenatal test for beta-hemoglobinopathies based on analyzing maternal plasma by using next generation sequencing.MethodsWe applied next generation sequencing (NGS) of maternal plasma to the non-invasive prenatal testing (NIPT) of autosomal recessive diseases, sickle cell disease and beta-thalassemia. Using the Illumina MiSeq, we sequenced plasma libraries obtained via a Twist Bioscience probe capture panel covering 4 Kb of chromosome 11, including the beta-globin (HBB) gene and >450 genomic single-nucleotide polymorphisms (SNPs) used to estimate the fetal fraction (FF). The FF is estimated by counting paternally transmitted allelic sequence reads present in the plasma but absent in the mother. We inferred fetal beta-globin genotypes by comparing the observed mutation (Mut) and reference (Ref) read ratios to those expected for the three possible fetal genotypes (Mut/Mut; Mut/Ref; Ref/Ref), based on the FF.ResultsWe bioinformatically enriched the FF by excluding reads over a specified length via in-silico size selection (ISS), favoring the shorter fetal reads, which increased fetal genotype prediction accuracy. Finally, we determined the parental HBB haplotypes, which allowed us to use the read ratios observed at linked SNPs to help predict the fetal genotype at the mutation site(s). We determined HBB haplotypes via Oxford Nanopore MinION sequencing of a 2.2 kb amplicon and aligned these sequences using Soft Genetics' NextGENe LR software.ConclusionThe combined use of ISS and HBB haplotypes enabled us to correctly predict fetal genotypes in cases where the prediction based on variant read ratios alone was incorrect.

The cause of death in people affected by sickle cell disease (SCD) is often challenging to define as prior studies have used retrospective or administrative data for analysis. We used a prospective longitudinal registry to assess mortality and clinical co-morbidities among subjects enrolled in the Sickle Cell Disease Implementation Consortium (SCDIC) registry. At enrollment, we collected the following data: patient-reported demographics, SCD phenotype, baseline laboratory values, comorbidities, and current medications. Subjects were followed for a median of 4.7 years before the present analysis. The relationship of clinical co-morbidities (at time of enrollment) to mortality was determined using survival analysis, adjusting for SCD phenotype and gender. There was a total of 2439 people with SCD enrolled in the SCDIC registry. One hundred and twenty-eight participants (5%) died during the observation period (2017-2022). Six people died from trauma and were excluded from further analysis. Proximate cause of death was unwitnessed in 17% of the deaths, but commonest causes of death include cardiac (18%), acute chest or respiratory failure (11%), sudden unexplained death (8%). Enrollment characteristics of the individuals who died (n = 122) were compared to those of survivors (n = 2317). Several co-morbidities at enrollment increased the odds of death on univariate analysis. All co-morbidities were included in a multivariable model. After backward elimination, iron overload, pulmonary hypertension, and depression, remained statistically significant predictors of the risk of death. SCD reduces life expectancy. Improved comprehensive and supportive care to prevent end-organ damage and address comorbidities is needed for this population.

AbstractSickle cell disease (SCD) is a genetic disorder affecting 100 000 people with an estimated annual medical cost of $3 billion in the United States; however, the economic impact on patients is not well described. We aimed to examine the indirect economic burden and test the hypothesis that socioeconomic status and greater social vulnerability risks are associated with increased absenteeism and employment loss. We surveyed adults and caregivers of children with SCD at 5 US centers from 2014 to 2021. Logistic regression models were used to examine the associations of employment loss and missed days of work with demographics and social determinants. Indirect costs were estimated by multiplying the self-reported missed days of work and job loss by 2022 average wages by the state of the participating institution. Of the 244 participants, 10.3% reported employment loss in the last 5 years, and 17.5% reported missing 10 or more days of work. Adults had 3 times more employment loss compared with caregivers of children with SCD (OR, 3.18; 95% CI, 1.12-9.01) but fewer missed days of work (OR, 0.24; 95% CI, 0.11-0.0.51). Participants who did not live with a partner reported increased employment loss (OR, 4.70; 95% CI, 1.04-21.17) and more missed days of work (OR, 4.58; 95% CI, 1.04-20.15). The estimated annual indirect economic burden was $2 266 873 ($9290 per participant). Adults with SCD and caregivers of children with SCD commonly report employment loss and missed days of work as important risk factors. The high indirect economic burden suggests that future economic evaluations of SCD should include SCD-related indirect economic burden.

Sickle cell disease (SCD) is a single gene blood disorder characterised by frequent episodes of pain, chronic anaemic, acute chest syndrome, severe disease complications and lifelong debilitating multi-system organ damage. Genetic testing and screening programs for SCD and the sickle cell trait (SCT) are valuable for early diagnosis and management of children living with SCD, and in the identification of carriers of SCT. People with SCT are for the most part asymptomatic and mainly identified as through genetic testing or when they have a child with SCD. This qualitative study explored perceptions towards genetic testing for SCD and SCT in Cameroon, Ghana, and Tanzania. The results show a general preference for newborn screening for SCD over prenatal and premarital/preconception testing, primarily due to its simpler decision-making process and lower risk for stigmatization. Premarital testing for SCT was perceived to be of low public health value, as couples are unlikely to alter their marriage plans despite being aware of their risk of having a child with SCD. Adolescents were identified as a more suitable population for SCT testing. In the case of prenatal testing, major concerns were centred on cultural, religious, and personal values on pregnancy termination. The study revealed a gender dimension to SCD/SCT testing. Participants mentionned that women bear a heightened burden of decision making in SCD/SCT testing, face a higher risk of rejection by potential in-laws/partners if the carriers of SCT, as well as the possibility of  divorce if they have a child with SCD. The study highlights the complex cultural, ethical, religious and social dynamics surrounding genetic testing for SCD and emphasises the need for public education on SCD and the necessity of incorporating genetic and psychosocial counselling into SCD/SCT testing programs.

Background Study Design and Methods Results Discussion Chronic red blood cell (RBC) transfusion is an established therapy to prevent stroke in patients with sickle cell anemia (SCA). It is unclear if adding daily hydroxyurea treatment to chronic transfusion is beneficial.We conducted a phase 2 clinical trial (NCT03644953) investigating the addition of dose‐escalated hydroxyurea to chronic transfusion for patients with SCA receiving simple chronic transfusion for stroke prevention. Simple chronic transfusion therapy was administered as per the same protocol before and after hydroxyurea treatment in which the volume transfused was dependent on the pretransfusion hemoglobin (Hb).A total of 14 participants enrolled with nine completing one year of combination hydroxyurea and transfusion (HAT) therapy after reaching hydroxyurea target dose. No participant who discontinued the study prematurely had a serious adverse event attributed to HAT. Among the nine participants who completed the study, eight participants achieved a reduction in RBC transfusion volume with a median reduction of −19.4 mL/kg/year (interquartile range −31.8, −2.8 mL/kg/year), p = .02, when comparing pre‐ and post‐HAT time periods. With the addition of hydroxyurea participants had a significant increase in pretransfusion Hb S% but this was balanced by an increased Hb F% and decreased lactate dehydrogenase. One participant developed a pretransfusion Hb >11 g/dL and Hb S > 45% that required holding hydroxyurea and changing to partial manual exchange transfusions. No patient had evidence of cerebrovascular disease progression.Hydroxyurea added to chronic transfusion therapy for patients with SCA is feasible and decreases RBC transfusion volume requirements. [ABSTRACT FROM AUTHOR]

Background: Sickle cell disease is a genetic disease with multisystem involvement. More than 300,000 children are born with sickle cell disease globally, with the majority of cases being in Sub-Saharan Africa. In Uganda, about 20,000 children are born with sickle cell disease annually, with more than three-quarters dying before the age of 5 years. Those who live beyond 5 years tend to have poor health-related quality of life, numerous complications, and recurrent hospitalizations. In developing countries, most symptomatic patients are diagnosed early in childhood. Few of those not screened in childhood tend to present in adulthood with variable symptoms. Case presentation: This case reports a 22-year-old African male patient of Toro tribe who presented with paroxysms of multiple joint pain associated with generalized body malaise for about 6 months. He presented as a referral from a lower facility with an unestablished cause of symptoms. Physical examination revealed conjunctival pallor, icterus, and tenderness of joints. Cell counts showed anemia and hemoglobin electrophoresis revealed 87% of sickled hemoglobin. Conclusion: This case report pinpoints the importance of considering the diagnosis of sickle cell disease even in adults presenting with symptoms of sickle cell disease. It also adds to the relevance of screening at all age groups, especially in high-endemic regions such as Africa and Asia. [ABSTRACT FROM AUTHOR]

Summary Depression, disrupted sleep and pain are common comorbidities in sickle cell disease. We tested (1) if these comorbidities are associated with attention/executive functioning, processing speed and instrumental activities of daily living (IADLs), which describe complex skills that support independence, and (2) if cognitive symptoms mediate the relationship between comorbidities and IADLs. Participants (n = 2417) completed patient‐reported outcome measures through the Sickle Cell Disease Implementation Consortium. Mean age of participants was 28 years and HbSS/Sβ0 genotypes were prevalent (73%). Comorbidities of depression, pain frequency and disrupted sleep were associated with processing speed and attention/executive functioning (all p < 0.01) when controlling for stroke and demographics. IADLs were associated with depression, pain, sleep, attention/executive functioning, income (<$25 000) (all p < 0.001) and genotype (p = 0.0025) after controlling for covariates. The indirect effects of attention/executive functioning and processing speed were both significant (p < 0.001) in mediation models that examined pathways between comorbidities and IADLs. Attention/executive functioning accounted for 17.5% of the relationship between depression and IADLs and sleep and IADLs. Processing speed explained 10% of the relationship between sleep and IADLs and 8% of the relationship between depression and IADLs. Managing comorbidities should be prioritized to mitigate cognitive symptoms and improve complex daily living skills. [ABSTRACT FROM AUTHOR]

Summary Hydroxycarbamide (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. [ABSTRACT FROM AUTHOR]

Summary Red blood cell (RBC) antigen matching beyond ABO and RhD is commonly recommended for patients with sickle cell disease (SCD) and thalassaemia. We present an updated systematic literature review to inform evidence‐based guidelines on RBC matching. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool was used to develop recommendations. Six new observational studies (4 prospective, 2 retrospective) were identified. The six studies reported on 583 patients in total, including cross‐over designs, with sample sizes from 10 to 343. Studies were heterogeneous, utilising varying degrees of RBC matching and different definitions for ‘extended’ matching. All reported on alloimmunisation. One study reported on molecular matching. The reported prevalence of alloimmunisation using limited matching was 0%–50% and with extended matching was 0%–24%. Eighty‐two patients were alloimmunised before study entry. The risk of bias across studies was moderate to critical. The guideline panel recommends that ABO, RhDCcEe, and K‐compatible RBCs are selected for individuals with SCD and thalassaemia, even in the absence of alloantibodies, and that RBCs which are antigen‐negative to already existing clinically significant antibodies are chosen. There is a need for comparative research to define the benefit, impact, cost‐effectiveness, and feasibility of extended RBC matching strategies to prevent alloimmunisation. [ABSTRACT FROM AUTHOR]

Introduction: The translational gap from the discovery of evidence-based solutions to their implementation in healthcare delivery organizations derives from an incorrect assumption that the need for change among executive, administrative, or clinical personnel is the same as the demand for change. For sickle cell disease (SCD), implementation of evidence-based guidelines is often delayed or obstructed due to lack of demand. This challenge allows for the persistence of resource limitations and care delivery models that do not meet the community's unique needs. Agile Storytelling is a process built on the scientific foundations of behavioral economics, complexity science, and network science to create local demand for the implementation of evidence-based solutions. Methods: Agile Storytelling includes a design phase and a testing phase. The design phase converts the evidence-based solution into a minimally viable story of a hero, a villain, struggle, drama, and a resolution. The testing phase evaluates the effectiveness of the story via a series of storytelling sprints in the target local healthcare delivery organization. The efficacy of Agile Storytelling was tested in an iterative n -of-1 case study design. Results: Agile Storytelling was used in a large, urban, healthcare system within the United States to facilitate implementation of national SCD best-practice guidelines. After repeated failures attempting to use national and local data regarding the high societal need to hire a SCD-specific social worker, an Agile change conductor using Agile Storytelling was able to create demand for the new position within a week. This decision has ultimately improved patient outcomes and led to the adoption of a specialized collaborative care team for SCD within the health network. Discussion: Agile Storytelling can lead to structured, effective, and informed storytelling to create local demand within healthcare delivery organizations. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion The study presents the risk of the maternal‐fetal morbidity and mortality among one of the largest cohort of sickle cell disease (SCD) pregnancies in India and reports the epidemiology of the maternal morbidity.This was a retrospective cohort study conducted at Kasturba Maternity Hospital, SEWA Rural, in the tribal area of Gujarat, India. All pregnant women admitted to the Hospital between 2016 and 2021 were screened for SCD, and their maternal‐fetal morbidities were recorded throughout the pregnancy. We quantified risk of maternal‐fetal morbidity and mortality among SCD, trait and normal pregnancies after adjusting for potential confounders using Poisson and logistic regression.A total of 24 256 delivered during the study period, with 354 (1.5%) and 4216 (17.4%) suffering from SCD and trait, respectively. After adjusting for potential confounders, the women with SCD pregnancy had higher risk of maternal death (adjusted‐odds‐ratio [AOR] 13.7, 95% CI: 4.5–42.7), anemia (AOR 6.8, 95% CI: 4.5–10.2), severe anemia (AOR 4.3, 95% CI: 3.3–5.6), preterm delivery (AOR 4.5, 95% CI: 3.6–5.7), cesarean section (AOR 5.5, 95% CI: 4.7–7.0), stillbirth (AOR 3.4, 95% CI: 2.3–5.3), and low birth weight (AOR 3.1, 95% CI: 2.4–39) compared to normal pregnancies. Maternal morbidities occurred throughout the pregnancy; however, the risk was highest during the last month of pregnancy. Pregnant women who had severe manifestation of SCD before the pregnancy were at higher risk of developing maternal morbidities.We concluded that SCD might be an independent risk‐factor for developing maternal‐fetal morbidities. The SCD pregnancies with prior severe manifestations must be carefully managed during the last month of pregnancy when the risk is highest. [ABSTRACT FROM AUTHOR]

Background Study Design and Methods Results Discussion Many children with sickle cell disease (SCD) who suffer a stroke receive chronic transfusion therapy (CTT) indefinitely; however, their adulthood neurologic outcomes have not been reported. Understanding these outcomes is critical to inform decisions regarding curative therapy in childhood.In this retrospective study, we described a cohort of adults with SCD and a history of childhood stroke who received care at a single center and compared their outcomes with matched subjects without childhood stroke using chi2 and Mann–Whitney U tests.Of 42 subjects with childhood stroke, all received CTT for secondary stroke prophylaxis. Five (11%) developed recurrent stroke. The rate of stroke was similar in subjects with and without childhood stroke (0.7 vs. 1.1 per 100 person·years, p = .63). Both cohorts exhibited evidence of iron overload (median ferritin 2227 vs. 1409 ng/dL, p = .10) and alloimmunization (45% vs. 45%, p = 1.0), despite receiving care in a comprehensive SCD program.For adults with SCD who had a childhood stroke, our results suggest CTT returns the risk of stroke to that of age‐matched stroke naïve patients with SCD. [ABSTRACT FROM AUTHOR]

AbstractSickle cell disease (SCD) is a prevalent inherited blood disorder arising from a single point mutation that results in substitution of valine with glutamic acid in the Beta hemoglobin chain, making red blood cells assume a banana shape under low oxygen state. It is most prevalent in sub-Saharan Africa, affecting approximately 2% of the population in Mali. This study aimed to evaluate the iron status and associated hematological parameters in SCD patients at steady state in an environment with a high prevalence of iron deficiency. A cross-sectional study was conducted at the Center de Recherche et de Lutte contre la Drépanocytose (CRLD) in Bamako, Mali, involving 757 SCD patients aged 10 to 29 years. Iron deficiency was defined as serum ferritin < 20 ng/mL, while iron overload was associated with serum ferritin > 500 ng/mL. The study population consisted of 171 (22.6%) hemolytic phenotypes (SS and Sβ0) and 586 (77.4%) viscous phenotypes (SC and Sβ+). Iron deficiency was found in 19 SCD patients (2.5%), with a higher prevalence in the SC phenotype (68.4%). All iron-deficient subjects exhibited microcytosis (MCV < 80 fL) and hypochromia (MCH < 26 pg). Hemoglobin levels < 12 g/dL were observed only in homozygous SCD patients. Low reticulocyte counts were noted in iron-deficient subjects with SC and Sβ+ phenotypes, but not in iron-deficient SS subjects. Serum C-reactive protein (CRP) was normal (< 10 mg/L) in all iron-deficient subjects, excluding iron deficiency due to chronic inflammation. Iron deficiency was observed among 2.5% of the study population, with a predominant occurrence among those with SC phenotype. All iron deficient subjects had microcytosis and hypochromia. Hemoglobin levels below 12 g/dL were only found in homozygous SCD patients. Additionally, low reticulocyte counts were noted in iron deficient patients with SC and Sβ+ phenotypes, though not in those with the SS phenotype. These findings contribute to the understanding of iron status in SCD patients in an African context and highlights the importance of monitoring iron levels in these population to prevent complications associated with iron deficiency or overload. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusions Acute Chest Syndrome (ACS) is the leading cause of death in children with sickle cell disease (SCD) in the US—about half of the children who develop ACS present initially with pain.Here, we studied biomarkers to differentiate ACS from vaso‐occlusive crises (VOC) in children with SCD who presented with pain to the emergency department (ED). We conducted a prospective cohort study of consecutive patients who presented to the ED with pain and were discharged with ACS or VOC between March, 2017 and February, 2020.We identified 7 patients with ACS and 19 patients with VOC. The two groups were comparable in age and sex. All patients with ACS had asthma versus 42% of the VOC group. The ACS group had lower weight and BMI z‐scores. Patients with ACS compared to VOC had significantly higher respiratory rates, lower O2 saturation, and longer hospital stays. They also had higher white blood cell count, glucose level (> 99 mg/dL), anion gap (> 9 mEq/L), sPLA2 (> 7 pg/mL), IFN‐γ (> 17.8 pg/mL), IL‐10 (1.54 pg/mL), and IL‐12 (> 0.5 pg/mL) levels.We identified biomarkers associated with ACS development in children with SCD presenting with pain that allow for earlier ACS interventions to reduce mortality and morbidity. [ABSTRACT FROM AUTHOR]

Summary This study evaluates the neurocognitive and electrophysiological effects of 1‐year memantine treatment in 14 adolescents and young adults (mean age 24 years) with sickle cell disease (SCD, incluing sickle cell anaemia and sickle cell β‐thalassemia), hypothesizing improvements in cognitive functions and neural processing. Participants underwent assessments using subtests from the Wechsler Intelligence Scale and a computerized task‐switching paradigm with concurrent event‐related potential (ERP) recordings, both before and after the treatment period. Assessments focused on processing speed, working memory, attention and executive function. ERP measurements targeted brain response changes during task switching. Memantine treatment enhanced cognitive test performance, especially in processing speed as shown by the Digit–Symbol Coding and Symbol‐Search tests. Results indicated improved visuospatial and graphomotor speed, working memory and attention. The task‐switching test revealed reduced error rates, suggesting decreased cognitive load and enhanced executive control. Electrophysiological changes in P1 and P3 amplitudes at frontal and parietal locations post‐treatment pointed to more efficient neural processing in tasks requiring cognitive flexibility. These preliminary findings from a Phase II clinical study serve as a ‘proof of concept’, exploring the feasibility and potential effectiveness of memantine treatment in SCD—a previously uninvestigated context. They support the rationale for more extensive investigations to confirm these results and assess memantine's broader effectiveness. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is a debilitating monogenic disease originating from mutations in the hemoglobin beta chain gene producing an abnormal hemoglobin HbS. The polymerization of HbS is responsible for the sickling of erythrocytes leading to anemia and vaso-occlusive events. Gene therapy is a promising treatment of SCD, and two different gene therapy drugs, using gene editing or gene transfer, have already reached the marketing stage. There is still a need to improve the efficacy of gene therapy in SCD, particularly when using anti-sickling beta-globin gene transfer strategies, which must outcompete the pathological HbS. One possibility is to increase transduction by inhibiting lentiviral restriction factors such as interferon-induced transmembrane proteins (IFITMs). This can be achieved by the addition of cyclosporin H (CsH) during the transduction process. This strategy was applied here in CD34+ hematopoietic progenitor and stem cells obtained from cord blood (CB). A first series of experiments with lentiviral vector coding for a green fluorescent protein (GFP) gene confirmed that the addition of CsH enhanced transgene expression levels and vector copy number per cell (VCN), while CD34+ cells remained viable and functional. Notably, the production of colony-forming cells (CFC) remained unaffected unless very high VCN values were reached. In a second step, CD34+ cells obtained from the CB of newborns with homozygous (n = 2) or heterozygous (n = 1) SCD mutations were transduced with the GLOBE-AS3 lentiviral vector coding for the HbAS3 anti-sickling beta globin. As with GFP, GLOBE-AS3 lentiviral transduction was clearly enhanced by CsH, leading to VCN > 2 and therapeutic levels of expression of the HbAS3. Moreover, the process did not affect the viability or functions of CFC. The combination of CB progenitors, the GLOBE-AS3 vector, and CsH is thus shown here to be a promising approach for the treatment of SCD. [ABSTRACT FROM AUTHOR]

Background: Acute chest syndrome (ACS) is the leading cause of mortality, accounting for 25% of all deaths among individuals with sickle cell disease (SCD). There is a lack of evidence‐based laboratory and clinical risk stratification guidelines for the diagnosis and management of ACS. Study Design and Methods: To better understand physician practices for the management of ACS in the United States, we created an ACS Working Group including hematology and transfusion medicine physicians from four different SCD treatment centers in the United States. The working group created a physician survey that included physician demographics and ACS diagnostic criteria that they had to rate. The survey also included three case scenarios to assess physician attitudes about the management of ACS. Management options included supportive and preventive strategies in addition to transfusion therapy options. Results: Out of 455 physicians who received the survey, 195 responded (response rate = 43%). The respondents were primarily hematology/oncology physicians. The responses showed wide variability among physicians in how diagnostic criteria for ACS are used and how physicians risk‐stratify ACS patients in their practice. The responses also reflected variability in the use of transfusions for ACS. Discussion: Based on our results, we conclude that ACS is diagnosed and managed inconsistently among expert physicians, especially in their transfusion practices due to a lack of consensus on risk stratification criteria. Our data suggest an urgent need for well‐designed prospective studies to provide evidence‐based guidelines and minimize management variability among physicians who care for individuals with SCD and ACS. [ABSTRACT FROM AUTHOR]

Summary: Background: Sickle cell disease (SCD) is a Mendelian disorder characterized by a point mutation in the β‐globin gene that leads to sickling of erythrocytes. Several studies have shown that absolute neutrophil count is strongly associated with clinical severity of SCD, suggesting an apparent role of white blood cells (WBC) in SCD pathology. However, the mechanism by which genetic variants lead to WBC count differences in SCD patients remains unclear. Methods: Genome‐wide association (GWA) analyses were carried out amongst a cohort of 2409 Brazil SCD participants. Association of WBC count and genetic markers were investigated in homozygous sickle cell anaemia participants and compound heterozygous sickle cell haemoglobin C participants. Results: GWA analysis showed that variants in genes TERT, ACKR1, and FAM3C are associated with WBC count variation. The well‐studied association between WBC count and Duffy null phenotype (variant in ACKR1) in healthy populations was replicated, reinforcing the influence of the SNP rs2814778 (T>C) in WBC count. Conclusion: Genetics plays an important role in regulating WBC count in patients with SCD. Our results point to possible mechanisms involved in WBC count variation and as increased WBC count is associated with more severe SCD, these results could suggest potential therapeutic targets for individuals with SCD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is one of the most devastating inherited haemoglobinopathy that affects mostly children. Its prevalence can reach up to 13 % in the south-eastern part of Madagascar. For socio-cultural and economic reasons, the majority of patients use plants to manage the symptoms of this genetic disease. This work aims to inventory these plants and collect all information on their use, their therapeutic effects, and their eventual side effects in order to compile a database. These plants will be the subject of future chemical, pharmacological and toxicological investigations in the laboratory. Semi-directive interviews were led among 208 respondents from January 2018 to January 2020 in the eastern part of Madagascar. After obtaining the informed consent of the interviewees, collected data on the used medicinal plants were analyzed for various ethnomedicinal parameters including frequency of citation (FC), use value (UV), relative frequency of citation (RFC), fidelity level (FL), family use value (FUV) and informant consensus factor (ICF) related to the SCD management and the other mentioned diseases. Among the 208 respondents, 30.29 % were male; 73.39 % received formal education; 53.37 % were farmers, 8.17 % were traditional healers and 6.73 % were herbal sellers. Most of them (94.23 %) have a good knowledge of SCD and 91.83 % of them use herbal medicine to manage SCD. They recommended 123 plant species belonging to 111 genera and 62 families. Asteraceae (14.50 %) was the most cited family however Blechnaceae was the most valued family (FUV = 0.356). The majority of the cited species (70.73 %) were wild plants. Herbs (42.28 %) were the most used plant life form and the most used common parts were leaves (44.68 %). They usually prepare tea by infusion of plant material (71.83 %). Ficus polita was the most important species with the highest FC (10.93 %), UV (0.393), RFC (75.92 %) and FL (94.94 %). ICF of SCD and its symptoms value was 0.50 showing the homogeneity, and the consensus among the informants in the use of medicinal plants for managing this disease. Some species (08) have been reported for their anti-sickling properties and some of the other species have been reported for their pharmacological properties related to SCD symptoms management. These results confirmed the importance of investigating the use of plant species to manage SCD and its symptoms in the eastern part of Madagascar, suggesting the fundamental role of ethnomedicinal studies for the sustainable use of plant species for future scientific investigations on phyto-drugs for SCD management. [Display omitted] • 123 plant species were cited in the management of SCD and/or its symptoms. • The majority (70.73 %) of them were wild plants. • Herbs (42.28 %) was the most used plant life form and the most used common parts were leaves (44.68 %) and aerial parts (25.53 %). • The majority of the herbal preparation was infusion (71.83 %) and the administration is only by oral route. • The knowledge of medicinal plants depends on the age and the occupation of the informants. • Ficus polita and Stenochlaena tenuifolia were the most important species according to their use value. • Among the 123 species, 8 species have been reported for their anti-sickling properties. [ABSTRACT FROM AUTHOR]

Objective To compare the risk of severe maternal morbidity (SMM) from the delivery admission to 42 days' postdischarge among persons with sickle cell disease (SCD) to those without SCD. Study Design This retrospective cohort study included deliveries ≥20 weeks' gestation at an urban safety net hospital in Atlanta, GA from 2011 to 2019. The exposure was SCD diagnosis. The outcome was a composite of SMM from the delivery admission to 42 days' postdischarge. SMM indicators as defined by the Centers for Disease Control and Prevention were identified using the International Classification of Diseases, Ninth and Tenth Revisions (ICD-9/10) codes; transfusion of blood products and sickle cell crisis were excluded. Results Of N = 17,354 delivery admissions, n = 92 (0.53%) had SCD. Persons with SCD versus without SCD had an increased risk of composite SMM (15.22 vs. 2.29%, p < 0.001), acute renal failure (6.52 vs. 0.71%, p < 0.001), acute respiratory distress syndrome (4.35 vs. 0.17%, p < 0.001), puerperal cerebrovascular disorders (3.26 vs. 0.10%, p < 0.001), sepsis (4.35 vs. 0.42%, p < 0.01), air and thrombotic embolism (5.43 vs. 0.10%, p < 0.001), and ventilation (2.17 vs. 0.09%, p < 0.01). Ultimately, those with SCD had an approximately 6-fold higher incidence risk ratio of SMM, which remained after adjustment for confounders (adjusted incidence risk ratio [aIRR]: 5.96, 95% confidence interval [CI]: 3.4–9.19, p < 0.001). Persons with SCD in active vaso-occlusive crisis at the delivery admission had an approximately 9-fold higher risk of SMM up to 42 days' postdischarge compared with those with SCD not in crisis at the delivery admission (incidence: 25.71 vs. 8.77%, p < 0.05; aIRR: 8.92, 95% CI: 4.5–10.04, p < 0.05). Among those with SCD, SMM at the delivery admission was primarily related to renal and cerebrovascular events, whereas most postpartum SMM was related to respiratory events or sepsis. Conclusion SCD is significantly associated with an increased risk of SMM during the delivery admission and through 42 days' postdischarge. Active crisis at delivery further increases the risk of SMM. Key Points Sickle cell disease was associated with an approximately 6-fold increased risk of SMM. Active vaso-occlusive crisis at delivery was associated with an approximately 9-fold increased risk of SMM. 48% of SMM events in persons with SCD occurred postpartum and were respiratory- or sepsis-related. [ABSTRACT FROM AUTHOR]

Genetic manipulation of hematopoietic stem cells (HSCs) is being developed as a therapeutic strategy for several inherited disorders. This field is rapidly evolving with several novel tools and techniques being employed to achieve desired genetic changes. While commercial products are now available for sickle cell disease, transfusion-dependent β-thalassemia, metachromatic leukodystrophy and adrenoleukodystrophy, several challenges remain in patient selection, HSC mobilization and collection, genetic manipulation of stem cells, conditioning, hematologic recovery and post-transplant complications, financial issues, equity of access and institutional and global preparedness. In this report, we explore the current state of development of these therapies and provide a comprehensive assessment of the challenges these therapies face as well as potential solutions. [ABSTRACT FROM AUTHOR]

Background: Sickle cell anemia (SCD) is a relatively uncommon health condition in many countries, but it is prevalent in Saudi Arabia mainly due to the high incidence of consanguineous marriages. Regrettably, there are elevated rates of vaso-occlusive crises (VOCs) and blood transfusions, leading to poor quality of life and significant financial strain. Objective(s): This study aimed to assess the frequency of blood transfusions, out-of-pocket expenditures (OOPEs), and health-related quality of life (HRQoL) in SCD patients. Methods: This was a questionnaire-based cross-sectional study that involved SCD patients at a university-affiliated tertiary care center in Riyadh, Saudi Arabia. The patients' medical and sociodemographic characteristics were obtained from the electronic medical records. Data on HRQoL and OOPEs were collected through a questionnaire-based interview. To present the baseline characteristics, descriptive statistics such as mean, standard deviation, frequency, and percentage were used. In addition, various statistical tests, including the Chi-Square test, Student t-test, one-way ANOVA, and multiple linear regression, were performed. Results: One hundred and eighteen patients consented to participate and were included in the analysis. Almost 53% of the patients were females. The mean age of the sample was 31 years, while the age-adjusted quality-adjusted life years (QALYs) was 24.33 years (p-value < 0.0001). Most patients (83.05%) reside in Riyadh with a monthly family income of less than USD 2666.67 (75.42%). Monthly OOPEs were, on average, USD 650.69 ± 1853.96, and one-third of the adult patients reported income loss due to illness, further exacerbating their financial strain. High frequency of blood transfusion (β = −0.0564, p-value = 0.0066) and higher number of comorbidities (β = −0.10367, p-value = 0.0244) were negatively associated with the HRQoL among adult patients. On the other hand, adult patients with higher levels of education had better HRQoL (β = 0.05378, p-value = 0.0377). Conclusions: The findings of this study highlight the negative impact of SCD on patients' HRQoL and financial well-being. This underscores the urgent need for comprehensive systemic approaches to address the challenges posed by SCD in Saudi Arabia. [ABSTRACT FROM AUTHOR]

Background: Ultrasonography is an established and reliable method for assessing the spleen. Because of variation due to genetic and other environmental factors including malaria endemicity, interpretation of spleen sizes requires a knowledge of the normal reference range for a given population. This study aimed to identify spleen size reference ranges across age groups of healthy controls to serve as a baseline to assess changes in spleen size in patients with sickle cell disease. Methods: Using a cross-sectional study design, spleen size was measured in healthy people of different age groups and steady-state sickle cell disease patients (children and adults) using abdominal ultrasonography. Using the age-group-specific reference values obtained from the controls, spleens were classified into small, normal size or enlarged among the sickle cell disease patients. Results: The study consisted of 109 (34.8%) healthy controls and 204 (65.2%) steady-state sickle cell disease patients. The spleen was visualised in all the controls (n = 109) and in 107 (52.4%) sickle cell disease patients. Using cut-off values for spleen length among the controls across age groups (< 5 years (5.0–7.0 cm); 5–9 years (5.5–8.5 cm); 10–14 years (6.0–11.0 cm) and ⩾ 15 years (7.0–12.5 cm)), spleen size was classified as small (n = 18/204; 8.87%), normal (n = 68/204; 33.3%) and enlarged (n = 21/204; 10.3%) among the sickle cell disease patients. Conclusion: Model-based age-group reference ranges and percentile curves for splenic dimensions based on ultrasonography among normal controls in North-Eastern Nigeria were established and may be of value in assessing spleen sizes among sickle cell disease patients living in malaria-endemic regions of Africa. [ABSTRACT FROM AUTHOR]

Objectives: High rate of alloimmunization in sickle cell disease (SCD) patients poses a significant challenge in finding compatible blood unit. Accurate determination of the blood group genotype of them can help reduce the alloimmunization risk. Tetra ARMS PCR is a novel method that has been utilized recently to investigate SNPs in diseases in a fast and reliable way. Methods: Our study included 104 SCD and sickle thalassemia (Sβ) patients referred to Baghaei-2-Hospital of Ahvaz in 2019 using a nonrandom sampling method. Blood samples were collected for serological and molecular tests. Rh genotyping was performed using Tetra ARMS PCR and compared with the serological results. Results: Based on the Tetra ARMS PCR method, out of 104 patients, 7 (6.7%) were d/d, 40 (38.5%) were D/d, 57 (54.8%) were D/D, 25 (24%) were C/C, 59 (56.7%) were C/c, 20 (19.3%) were c/c, 4 (3.8%) were E/E, 25 (24%) were E/e, and patients 75 (72.2%) were e/e. There were discrepancies in the serological and molecular results for 11 patients. Conclusion: Use of Tetra ARMS PCR in combination with serological methods for determining the Rh blood group system in donors and transfusion-dependent patients represents a remarkable transformation in the field of immunohematology. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Methods Results Conclusions Access to crizanlizumab, a disease‐modifying therapy for sickle cell disease (SCD), was provided through a managed access program (MAP, NCT03720626). The present analysis evaluated the impact of 12 months of crizanlizumab treatment on vaso‐occlusive crises (VOCs), and on the use of opioids for VOC‐related pain relief, in patients with SCD from the MAP.From June 2018 to January 2023, 112 patients with a history of recurrent VOCs completed 12 months of crizanlizumab (5 mg/kg) treatment and were monitored for adverse events (AEs).Crizanlizumab led to reductions of 18.0% and 36.2% in the proportions of patients having ≥ 1 home‐ and ≥ 1 healthcare‐managed VOCs. Median absolute changes (interquartile range) from baseline in the rates of home‐ and healthcare‐managed VOCs were −3.0 (−6.0, −1.0) and −2.0 (−4.0, 0), respectively. Data stratified by genotype and prior hydroxyurea use showed similar reductions in VOC rates. A 35.5% reduction in the proportion of patients requiring opioids was noted. AEs were consistent with earlier reports, and no new safety concerns were identified.Crizanlizumab demonstrated potential benefits in attenuating VOC episodes, irrespective of SCD genotype and prior hydroxyurea use, and in lowering opioid usage. The safety of crizanlizumab was consistent with earlier reports.Trial Registration: The MAP has been registered at ClinicalTrials.gov with the ID, NCT03720626 [ABSTRACT FROM AUTHOR]

Summary Sickle cell disease (SCD) with vaso‐occlusive pain crisis (VOC) significantly impacts patient well‐being and often results in extensive healthcare resource utilization. This study assessed the VOC burden, its management and its impact on patients' quality of life (QoL). A cross‐sectional observational study was conducted between November 2021 and June 2022, including 1000 SCD patients from high‐prevalence states in India. Data on demographics, clinical characteristics, VOC severity, management and QoL were collected. The study revealed that 33.5% of patients reported at least one VOC episode during the study period. In the year prior to their enrolment, 836 (83.60%) patients reported at least one VOC episode, with an equal proportion of 407/487 (83.6%) adults and 429/513 (83.6%) paediatric patients, reducing their QoL across all domains compared to patients without VOC. Of these, 469/1000 patients (46.9%) experienced ≥3 VOC episodes. Additionally, 764/1000 (76.40%) patients managed their VOCs at healthcare facilities, with 501/1000 (50.1%) requiring inpatient admissions. Further, 71.80% of patients received Hydroxyurea (HU) therapy. The study depicts the severity of the Arab–Indian haplotype in Indian SCD patients visiting healthcare settings based on high VOC burden. This highlights the urgent need for better management strategies and resource allocation for these patients. [ABSTRACT FROM AUTHOR]

AbstractObjectiveMethodsResultsConclusionsThis 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.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.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.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. [ABSTRACT FROM AUTHOR]

Importance: While the prevalence and impact of depression have been widely described in sickle cell disease, its relationship with precariousness has never been studied. Objective: This study aimed to describe the prevalence of depression and its relationship with clinical and demographic factors including social precariousness in children with sickle cell disease in French Guiana. Methods: We included children aged 12–18 years with sickle cell disease from the Sickle Cell Reference Center in French Guiana. A simple depression questionnaire "Child depression inventory 2" was proposed and completed by a clinical examination and consultation by a psychologist. Using the known assessment of health inequalities and poverty in health screening centres (EPICES) score, we developed a composite precariousness score that uses five items (each item is scored from 0 to 2). According to the chosen items, precariousness was defined as a score ≥5. Results: The prevalence of depression was 42.5% [95% CI: 31.5–54]. The median age was 15 years [95% CI: 13–17]. The age distribution peaked at 14 years in patients with depression. There were 76% of precarious patients in the depressed group and 18% in the control group (p < 0.0001). In multivariate analysis, genotype SC (OR = 7.66, [1.17; 50.13], p = 0.0338) and precariousness (OR = 15.68, [4.73; 51.94], p < 0.0001) were associated with higher rates of depression. Baseline hemoglobin levels (OR = 0.48, [0.27; 0.88], p = 0.0173) were also associated with lower rates of depression. Conclusions and Relevance: Despite free healthcare, precariousness is an independent risk factor for depression. [ABSTRACT FROM AUTHOR]

Background and Objectives Materials and Methods Results Conclusion This review aims to explore the impact of sickle cell disease (SCD) on patients' quality of life (QoL) and the effectiveness of different transfusion modalities, particularly automated red blood cell exchange (aRBCX), in managing the factors that impact QoL.A systematic search was performed in PubMed to retrieve articles with data on QoL in SCD patients treated with aRBCX during the last 20 years. A targeted search for medical guidelines and a free search were added.When assessing the impact of the transfusion modality on the QoL of patients with SCD, some studies indicated an improvement in health‐related QoL when using aRBCX while others reported no differences. The benefits of aRBCX include a decrease in length of hospital stay, pain‐related hospitalizations and procedure time. The drawbacks of aRBCX were also identified, including an increased number of procedure‐related complications (despite the overall number of complications showing no significant differences) and a more complex vascular access. Chronic red blood cell exchange favours psychosocial factors such as anxiety and social functioning, but the impact of using aRBCX in these parameters is not determined yet.aRBCX, known to be an efficient procedure to manage SCD, appears to be promising in improving patients' QoL. However, more comprehensive studies incorporating patient‐reported outcomes are needed to fully understand the impact of different transfusion modalities on QoL in SCD patients. An integrated care approach, including psychological support and pain management, may further enhance QoL. [ABSTRACT FROM AUTHOR]

Summary Allogeneic haematopoietic cell transplantation (HCT) with HLA‐matched sibling donor remains the most established curative therapeutic option for patients with sickle cell disease (SCD). However, it is not without risks, highlighting the need for a risk stratification system. Utilizing a machine learning (ML) approach that combines clinical and imaging variables, we identified red cell distribution width and renal organ damage as important risk factors for patients undergoing HCT. This ML‐based algorithm, similar to an approach previously reported for predicting mortality in patients with SCD, should be applicable to risk factor discovery in similar studies. [ABSTRACT FROM AUTHOR]

Background and Objectives: Hydroxyurea (HU) is an effective medication used to reduce the frequency of painful crises associated with sickle cell disease (SCD). However, data describing its prevalence among SCD patients in the Eastern Region of Saudi Arabia are scarce. This is a multi-center, retrospective, cross-sectional study that aims to investigate the pattern of prescribing HU in SCD patients and to determine the association between prescribing HU and other co-prescribed medications used to manage SCD complications. Methods: Data were collected from patients who visited the hematology clinics of Al-Qatif Central Hospital (QCH) and King Fahad Hospital in Hofuf (KFHH) between June 2021 to May 2023. The data included demographics, prescribed medications, and recent laboratory test results, all of which were collected from patients' medical records. Descriptive statistics were utilized to assess the difference between HU users vs. non-users. A binary logistic regression model was used to determine the association between prescribing HU and co-prescribed medications used to manage SCD complications. The results are presented as the odds ratio (OR) and 95% confidence interval (95% CI). Results: This study included 2816 SCD patients with a 56% prevalence of HU prescription. HU was prescribed for young age groups more often compared to old age group patients. Young males were more likely to be prescribed with HU compared to females, and it becomes dominant in females after the age of 36. HU users were more likely to have paracetamol (69% vs. 53%, OR = 1.9, 95% CI 1.6–2.2), NSAIDs (50% vs. 35%, OR = 1.7, 95% CI 1.5–2), and opioids (41% vs. 37%, OR = 1.3, 95% CI 1.1–1.6) co-prescribed, and less often to have laxatives (8% vs. 5%, OR = 0.66, 95% CI 0.48–0.9) and anticoagulants (22% vs. 15%, OR = 0.56, 95% CI 0.46–0.68) co-prescribed compared to non-users. Conclusions: The pattern of prescribing HU, supported by the association findings, raises concerns about patients' compliance and adherence to HU therapy. Early health education, specifically to young female SCD patients, is warranted to increase the success rate of HU therapy. [ABSTRACT FROM AUTHOR]

Background: Sickle cell hepatopathy (SCH) is a relatively uncommon complication of sickle cell disease (SCD), yet it does not accommodate variations in presentation, outcome, or severity according to age. Aim: To present SCH characteristics and assess the effect of implementation of a high-suspicion systematic diagnostic approach and early intervention plan of management. Methods: This case series presented the characteristics of five children with SCD with variable hepatic manifestation and implemented a diagnostic approach that included testing the transaminases and bilirubin in any patient with any suspicion of liver affection. Results: The five patients had a complicated SCD history. They all presented with fever, abdominal pain, and deepening of jaundice. The final diagnosis was reached with a more individualized approach; two had significant coagulopathy and were diagnosed with sickle cell intrahepatic cholestasis, while one had normal synthetic functions of the liver with rising transaminases and bilirubin levels, as well as high titer of Epstein–Barr virus diagnosed as acute viral hepatitis complicated with sickle cell hepatic crisis. One other patient had markedly elevated bilirubin with mild elevation of transaminases, and magnetic resonance cholangiopancreatography showed acute extrahepatic biliary dilatation treated by endoscopic removal of the stone. The fifth patient proved to have portal vein thrombosis by portal duplex causing portal hypertension and decompensated liver. The management plan included early exchange transfusion to keep their hemoglobin S (HbS) below 15% which was performed in three of the patients, in addition to aggressive supportive measures for correction of coagulopathy with full recovery and normalization of their liver functions. Conclusion: Despite the diagnostic challenges, the lack of standard diagnostic criteria, and the overlapping clinical presentation of SCH, the management and outcomes improved by following a systematic diagnostic approach. [ABSTRACT FROM AUTHOR]

Background Study Design and Methods Results Discussion With chronic transfusion in sickle cell disease (SCD), equipoise exists regarding whether increasing the post‐procedure hematocrit (Hct) suppresses endogenous erythropoiesis. Reticulocytosis predicts SCD morbidity and mortality, so this study's objective was to clarify the role of the post‐procedure Hct in suppressing reticulocytosis and to identify other potential red cell exchange (RCE) parameters predictive of reticulocytosis.This retrospective analysis of 17 patients who underwent chronic RCE at a single institution between 2014 and 2022 examined both standard red cell exchanges (SRCE) and exchanges preceded by isovolemic hemodilution (IVH‐RCE). Post‐procedure parameters with biologic plausibility to influence the subsequent procedure's absolute reticulocyte count (sPre‐ARC) were examined using regression modeling.Neither post‐hematocrit, nor post‐hemoglobin (Hb), nor ΔHb/day was associated with sPre‐ARC or the change in HbS% per day (ΔHbS%/day). Concurrent Hb was predictive for SRCE but not IVH‐RCE, where ARC trended lower than with SRCE. Male gender and post‐procedure neutrophil and white cell counts were predictors of sPre‐ARC, consistent with their associations with SCD morbidity and mortality. IVH‐RCE had a stronger correlation than standard RCE between pre‐Hct and neutrophil or white cell depletion.Although targeting a post‐procedure Hct maintains a higher subsequent pre‐procedure Hb and a lower sPre‐HbS%, it does not lead to sustained suppression of reticulocytosis as measured by the sPre‐ARC or the ΔHbS%/day. IVH‐RCE or the addition of hydroxyurea could be considered in those patients with high reticulocyte, white blood cell, or neutrophil counts. [ABSTRACT FROM AUTHOR]

Background: Sickle cell disease (SCD) is the most common hemoglobinopathy worldwide, characterized by vaso-occlusive crises and ischemia that affects patients on a multi-system level. Despite being a genetically simple disease due to a single base mutation, SCD poses many therapeutic challenges. Additionally, its impact on patients' life remains significant. This narrative review aims to provide a snapshot of recent highlights of the significant progress in SCD therapy, and the impact of SCD on patients' life, including the complications, morbidity, and mortality factors of the disease. Methodology: Google Scholar and PubMed were searched for "sickle cell disease". Only full-text English language original research articles were included in this review. In total, 600 articles were screened, 300 from each database, which were published from 2020 to 2024-06-01. A total of 139 studies were included in this review, after screening for inclusion. Conclusions: The increasing global incidence of sickle cell disease underscores the urgency for healthcare interventions to address the health challenges of an aging population living with this chronic condition. While treatment options for sickle cell disease have broadened, their availability is still limited. Among these options, stem cell transplant stands out as the definitive treatment, with ongoing efforts to enhance the donor pool. The disease significantly affects patients' quality of life and overall health, with emerging neurological and psychiatric issues. Additionally, the impact of sickle cell disease on reproductive health in both men and women presents a pressing need for further research to meet reproductive challenges. [ABSTRACT FROM AUTHOR]

Acute and chronic pain are the most frequent complications of sickle cell disease (SCD), often severely reducing quality of life and requiring management with long-term pharmacological interventions. A biopsychosocial approach conceptualizing pain in SCD as the result of complex biological, psychological, and social factors could facilitate targeted behavioral interventions. Mindfulness is one procedure for management of pain in individuals with chronic pain/illness. The goal of the current project was to design and implement a bedside mindfulness intervention to help patients with SCD enhance self-efficacy of pain management and reduce distress. As part of a quality improvement project in SCD clinics in a large health system, we developed a bedside mindfulness intervention to be provided during infusion sessions for patients presenting for acute vaso-occlusive episodes (VOE). The approach to development and implementation involved engagement of professionals working directly with patients. Concept planning meetings with these professionals along with qualitative patient and provider feedback informed feasibility, design, and intervention application. During a quantitative phase, patients completed validated surveys items on acceptability. Interview data (N = 11) supported patient interest in mindfulness skills and highlighted a need for tailored, person-centered interventions and non-pharmacological treatment strategies. On quantitative items, participants (N = 14) liked the intervention and agreed mindfulness skills would help manage disease-related distress. Following the interventions, participants reported increased mindfulness (p = .005). While preliminary, these results provide support for the continued development of evidence-based, mindfulness-oriented services to help individuals with SCD manage pain and other psychological difficulties. [ABSTRACT FROM AUTHOR]

Summary: Sickle cell disease (SCD) is a complex genetic blood disorder characterized by abnormal haemoglobin, resulting in sickle‐shaped red blood cells. While extensive research has concentrated on the genetic and physiological aspects of SCD, recent studies suggest a potential role of the human microbiome in SCD pathophysiology, adding new dimensions to its understanding. This review synthesizes current knowledge on the microbiome's involvement in SCD, focusing on alterations in the gut microbiome composition and diversity compared to healthy individuals, and their implications for disease pathogenesis. We explore how microbiome changes may contribute to vaso‐occlusive crises and other complications, along with the possible associations of specific microbial taxa or markers with disease crises and clinical outcomes. Additionally, we discuss the potential of microbiome‐targeted interventions, including probiotics, dietary modifications, and faecal microbiota transplantation, in managing SCD complications and improving patient outcomes. Understanding the intricate relationship between the microbiome and SCD could lead to innovative therapeutic strategies and personalized interventions for better managing the disease. This review underscores the importance of further microbiome research and its integration into holistic SCD care. [ABSTRACT FROM AUTHOR]

Summary: Optimal targets for red blood cell exchange (RCE) are not well defined in the chronic management of sickle cell disease. We analysed transfusion requirements and iron‐related outcomes in 101 patients on chronic RCE with a post‐procedure haematocrit (Ht) targeted at 34%, which is higher than typically used. A majority were of HbSS/HbSβ0 genotype (n = 72) and enrolled for neurological complications (n = 53). Fifty patients had a positive Ht balance with RCE (>2% mean increase from pre‐procedure level), while 43 patients maintained a neutral balance. The first group required fewer red blood cell units/year (65 vs. 80, p < 0.001), but a significant proportion were iron overloaded based on R2* with liver MRI (32% vs. none performed) and prescription of iron chelation (52% vs. 0%, p < 0.001, after a median of 19 months). The second group was more likely to receive iron supplementation (6% vs. 56%, p < 0.001). Chronic automated RCE with a post‐procedure Ht targeted at 34% is not iron‐neutral, and personalized Ht goals may be more appropriate in certain settings. This higher target should be compared with a lower Ht strategy in individuals with similar baseline red cell volumes to assess iron homeostasis and blood product requirements. [ABSTRACT FROM AUTHOR]

Summary: Viscosity–vaso‐occlusion (VVO) and haemolysis–endothelial dysfunction (HED) are pathophysiological mechanisms and clinical subphenotypes of sickle cell disease (SCD). Recurrent vaso‐occlusive crises (VOC) may lead to neuroplastic changes and pain sensitization. Among 257 SCD participants, we assessed the relationship of subphenotypes with pain sensitivity using quantitative sensory testing to identify heat pain thresholds (HPT) and pressure pain thresholds (PPT). VOC history and sleep, social and emotional functioning were assessed using the Adult Sickle Cell Quality of Life Measurement Information System. The 'elbow method' determined the optimal number of clusters as three. Clustering was performed using K‐prototypes. Among clusters 2 and 3, VOC frequency and severity were higher. Clusters 1 and 3 had lower haemoglobin, higher reticulocytes and lactate dehydrogenase and more leg ulcers. In multivariate regression, cluster 3 was associated with approximately 13.6% lower PPT compared to cluster 1, and female sex was associated with decreases in PPT and HPT at the hands and feet (p < 0.001). Hydroxyurea use and unit increases in sleep functioning and age were associated with approximately 20.1% higher foot‐PPT, 6.8% higher hand‐PPT and 2.5% higher hand‐HPT and foot‐HPT respectively. Findings suggest that a third subphenotype with mixed VVO and HED features and worse pain sensitization may exist. [ABSTRACT FROM AUTHOR]

The present study compares postoperative outcomes between patients with and without sickle cell disease (SCD) undergoing 1-to 3-level lumbar spinal fusion for degenerative pathologies. Patients who underwent 1-to 3-level lumbar spinal fusion for degenerative pathologies from 2010 to 2021 were identified using the PearlDiver database. Patients were separated into 1) SCD and 2) non-SCD groups and were propensity-matched 1:1 for age, sex, Elixhauser Comorbidity Index, surgical approach, and various comorbidities. Complications were separately analyzed by single- and multilevel procedures using chi-squared and Mann–Whitney U testing. Propensity-score matching identified 1934 SCD and non-SCD patients who underwent single-level fusion and 2094 SCD and non-SCD patients who underwent multilevel fusion. Across single-level fusions, those with SCD had a significantly higher risk of neurovascular compromise (P < 0.001), venous thromboembolism (P = 0.004), pneumonia (P = 0.032), urinary tract infections (P = 0.001), and greater postoperative opioid usage out to 12 months (P = 0.018). Across multilevel fusions, SCD carried higher risk for neurovascular compromise (P < 0.001), pneumonia (P = 0.010), and urinary tract infections (P < 0.001). All SCD patients had significantly higher opioid use at 1 month (P = 0.001) and at 6 months (P = 0.009) postoperatively. Patients with SCD undergoing lumbar spinal fusion demonstrate higher risks for coagulopathic, ischemic, and infectious-related complications, as well as long-term postoperative opioid use. Awareness of the unique complication profile in SCD patients may help guide surgeons in refining perioperative management strategies to optimize outcomes in patients with SCD. [ABSTRACT FROM AUTHOR]

Introduction: Skull infarction is an uncommonly reported complication of sickle cell disease. We aimed to characterize the clinical and imaging features of skull infarction in pediatric patients with sickle cell disease. Methods: We searched the PubMed database for case reports on skull bone infarction in pediatric patients with sickle cell disease. Out of 67 records retrieved, 15 met inclusion criteria, and a 16th case reported by the senior author was included. We extracted and analyzed clinical and imaging data. Results: The most common symptom at onset was headache (88%). Bilateral skull infarction (50%) and parietal bone involvement (82%) were frequent imaging findings. Epidural hematoma developed in 65% of the cases, 30% of patients required drainage, and exchange infusion was reported in 18%. No fatal outcomes were reported. Conclusions: Skull infarction is a potentially severe complication of sickle cell disease presenting unique clinical challenges. Acute headaches should raise suspicion for this condition and may require additional investigation. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Sickle cell disease (SCD) is a global hemoglobinopathy; approximately 300 000 individuals are diagnosed annually. Acute chest syndrome (ACS), a common complication, leads to significant hospitalization and mortality, particularly in cases of severe respiratory distress. ECMO outcomes in this specific population are poorly described.This retrospective observational study, utilizing data from the Extracorporeal Life Support Organization (ELSO) registry, focuses on children and young adults (<40 years) with SCD undergoing ECMO from 1998 to 2022.We observed a growing trend in ECMO cases over the last 15 years, with 210 SCD patients identified in the registry (five neonates, 95 children, 110 adults). ECMO was predominantly initiated for pulmonary support (62%), and most of the primary diagnoses were related to SCD (reported as “SCD” or “acute chest syndrome”). The global survival rate was 55.8% (59% for children and 52.7% for adults). None of the children supported for extracorporeal cardiopulmonary resuscitation survived, and only 2/18 (11%) of adults cannulated for ECPR survived. Complication rates, including acute renal failure (33.8%) neurological events (13%), thrombotic (23.3%), or bleeding events (22.9%) were not noticeably different from reported outcomes in the ELSO registry.Our findings suggest that ECMO outcomes in SCD patients align with general ECMO trends and may not be limited by suspected unfavorable results in children and young adults. Despite limitations, our study contributes valuable insights into using ECMO in SCD, emphasizing the need for further research and understanding in this underexplored domain. [ABSTRACT FROM AUTHOR]

Objective: Sickle cell disease (SCD), the most common inherited blood disorder in the United States, is associated with severe psychoneurological symptoms. While epigenetic age acceleration has been linked to psychoneurological symptom burden in other diseases, this connection is unexplored in SCD. This study aimed to assess the association between epigenetic age acceleration and psychoneurological symptom burden in SCD. Methods: In this cross-sectional study, emotional impact, pain impact, sleep impact, social functioning, and cognitive function were assessed in 87 adults living with SCD. DNA methylation data were generated from blood specimens and used to calculate epigenetic age using five clocks (Horvath, Hannum, PhenoAge, GrimAge, & DunedinPACE). Associations between epigenetic age acceleration and symptoms were assessed. Results: The sample (N = 87) had a mean (SD) chronologic age was 30.6 (8.1) years. Epigenetic age acceleration was associated with several symptom outcomes. GrimAge age acceleration (β = −0.49, p =.03) and increased DunedinPACE (β = −2.23, p =.004) were associated with worse emotional impact scores. PhenoAge (β = −0.32, p =.04) and the GrimAge (β = −0.48, p =.05) age acceleration were associated with worse pain impact scores. Increased DunedinPACE (β = −2.07 p =.04) were associated with worse sleep impact scores. Increased DunedinPACE (β = −2.87, p =.005) was associated with worse social functioning scores. We did not find associations between epigenetic age acceleration and cognitive function in this sample. Conclusion: Epigenetic age acceleration was associated with worse symptom experiences, suggesting the potential for epigenetic age acceleration as a biomarker to aid in risk stratification or targets for intervention to mitigate symptom burden in SCD. [ABSTRACT FROM AUTHOR]

In patients with sickle cell disease (SCD) and beta-thalassemia major (TM), allogeneic hematopoietic stem cell transplantation (HSCT) was considered the only curative treatment option with a good survival rate. However, with the recent approval of gene therapies, more information is needed to understand the benefits and risks of these interventions. We performed a retrospective analysis of the Kids Inpatient Database to describe demographic features, short-term complications, and hospital charges of patients with SCD and TM treated with HSCT during 2006–2019 in the United States. The database was filtered using the International Classification of Diseases, 9th and 10th edition codes to identify children under 20 years of age with SCD or TM who underwent HSCT. A total of 513 children with SCD or TM who received HSCT were analyzed. The prevalence of HSCT per 1000,000 U.S. population increased from 0.31 in 2006 to 1.99 in 2019 (p < 0.001). The median age of children with SCD who underwent HSCT was 10 (6–15) years, and that for TM was 6 (3–11.5) years (p < 0.001). The combined mortality rate was 4% (2.4%–6.6%) but higher in the TM group. The length-of-stay and total charges were higher in the TM population (p < 0.01). This study provides national data on HSCT among hospitalized children with SCD and TM in the United States, demonstrating an increasing use of HSCT between 2006 and 2019. Although hospital mortality of HSCT in these conditions is low, it still represents a challenge, especially in TM patients. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is well recognized as a hypercoagulablestate, however, it remains unclear whether a subgroup of children with SCD at higher risk of venous thromboembolic event (VTE) during hospitalization may benefit from thromboprophylaxis. Our objectives were to describe the clinical characteristics, outcomes and recurrence of hospital acquired VTE in patients with SCD younger than 21 years. This was a single center retrospective study. Data regarding demographics, reason for admission, location of VTE, risk factors like central venous catheter (CVC), intensive care unit (ICU) admission among others were extracted from electronic medical records over a 10-year study period (2011–2021). Recurrence of VTE at 1 and 5 years was assessed. Descriptive statistics were used as indicated. We identified a total of 20 VTE events over the 10-year study period. Six of these events occurred in those younger than 12 years of age. Fourteen (70%) VTE events occurred in the HbSS or HbSβThal0 genotypes compared to 6 (30%) in HbSC. Most common VTE was isolated pulmonary embolism (PE) (n = 10, 50%). VTE were most often associated with acute chest syndrome (ACS) (n = 14, 70%), ICU admissions (n = 10, 50%) and CVC (n = 5/9, 55%). One patient died from the VTE event. One patient with additional underlying risk factors had a recurrent VTE at 13 months. Our study suggests that ICU admission, ACS and presence of CVC increases the risk of VTE in children and young adults with SCD, but larger studies are indicated to validate our findings. [ABSTRACT FROM AUTHOR]