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BIVV003 is a gene-edited autologous cell therapy in clinical development for the potential treatment of sickle cell disease (SCD). Hematopoietic stem cells (HSC) are genetically modified with mRNA encoding zinc finger nucleases (ZFN) that target and disrupt a specific regulatory GATAA motif in the BCL11A erythroid enhancer to reactivate fetal hemoglobin (HbF). We characterized ZFN-edited HSC from healthy donors and donors with SCD. Results of preclinical studies show that ZFN-mediated editing is highly efficient, with enriched biallelic editing and high frequency of on-target indels, producing HSC capable of long-term multilineage engraftment in vivo, and express HbF in erythroid progeny. Interim results from the Phase 1/2 PRECIZN-1 study demonstrated that BIVV003 was well-tolerated in seven participants with SCD, of whom five of the six with more than 3 months of follow-up displayed increased total hemoglobin and HbF, and no severe vaso-occlusive crises. Our data suggest BIVV003 represents a compelling and novel cell therapy for the potential treatment of SCD.

Etavopivat is an investigational, once daily, oral, selective erythrocyte pyruvate kinase (PKR) activator. A multicenter, randomized, placebo-controlled, double-blind, 3-part, phase 1 study was conducted to characterize the safety and clinical activity of etavopivat. Thirty-six patients with sickle cell disease (SCD) were enrolled into 4 cohorts: 1 single-dose, 2 multiple ascending doses, and 1 open-label (OL). In the OL cohort, 15 patients (median age 33.0 years [range, 17-55]) received 400 mg etavopivat once daily for 12 weeks; 14 patients completed treatment. Consistent with the mechanism of PKR activation, increases in adenosine triphosphate and decreases in 2,3-diphosphoglycerate were observed and sustained over 12 weeks treatment. This translated clinically to an increase in hemoglobin (Hb; mean maximal increase 1.6 g/dL [range, 0.8-2.8]), with >1 g/dL increase in 11 (73%) patients during treatment. In addition, the oxygen tension at which Hb is 50% saturated was reduced (P = .0007) with a concomitant shift in point of sickling (P = .0034) to lower oxygen tension in oxygen-gradient ektacytometry. Hemolysis markers (absolute reticulocyte count, indirect bilirubin, and lactate dehydrogenase) decreased from baseline, along with matrix metalloproteinase-9 and erythropoietin. In the OL cohort, adverse events (AEs) were mostly grade 1/2, consistent with underlying SCD; 5 patients had serious AEs. Vaso-occlusive pain episode was the most common treatment-emergent AE (n = 7) in the OL cohort. In this, to our knowledge, the first study of etavopivat in SCD, 400 mg once daily for 12 weeks was well tolerated, resulting in rapid and sustained increases in Hb, improved red blood cell physiology, and decreased hemolysis. This trial was registered at www.ClinicalTrials.gov as #NCT03815695.

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.

Somatic gene therapy will be one of the most exciting practices of genetic medicine in Africa and is primed to offer a new life for persons living with sickle cell disease (SCD). Recently, successful gene therapy trials for SCD in the USA have sparked a ray of hope within the SCD community in Africa. However, the high cost, estimated to exceed 1.5 million USD, continues to be a major concern for many stakeholders. While affordability is a key global health equity consideration, it is equally important to reflect on other ethical, legal and social issues (ELSIs) that may impact the responsible implementation of gene therapy for SCD in Africa. These include informed consent comprehension, risk of therapeutic misestimation and optimistic bias; priorities for SCD therapy trials; dearth of ethical and regulatory oversight for gene therapy in many African countries; identifying a favourable risk-benefit ratio; criteria for the selection of trial participants; decisional conflict in consent; standards of care; bounded justice; and genetic tourism. Given these ELSIs, we suggest that researchers, pharma, funders, global health agencies, ethics committees, science councils and SCD patient support/advocacy groups should work together to co-develop: (1) patient-centric governance for gene therapy in Africa, (2) public engagement and education materials, and (3) decision making toolkits for trial participants. It is also critical to establish harmonised ethical and regulatory frameworks for gene therapy in Africa, and for global health agencies to accelerate access to basic care for SCD in Africa, while simultaneously strengthening capacity for gene therapy.

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.

Background: The aim of this study was to evaluate the clinical significance of blood-cell associated inflammation markers in patients with sickle cell disease (SCD) and sickle cell retinopathy (SCR). Methods: Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR), systemic immune inflammation index (SIII), systemic inflammation response index (SIRI), systemic inflammation modulation index (SIMI) and aggregate systemic inflammation index (AISI) were calculated. This study included 45 healthy controls (Group 1) and 100 SCD (Group 2). Patients in Group 2 were then divided into two groups: without SCR (Group 3) and with SCR (Group 4), and patients with SCR (Group 4) were further divided into two groups: non-proliferative sickle cell retinopathy (NPSCR) (Group 5) and proliferative sickle cell retinopathy (PSCR) (Group 6). Results: The mean values for NLR, PLR, SIII, SIRI, AISI, and SIMI were significantly higher in Group 2 compared to Group 1 (p = 0.011 for NLR, p = 0.004 for SIII, and p < 0.001 for others). Furthermore, AISI and SIMI parameters demonstrated statistically significant discriminatory power to distinguish Group 5 from Group 6 (p = 0.0016 and p = 0.0006, respectively). Conclusion: Given the critical role of inflammatory mechanisms in the pathogenesis of SCD and its related complications, the assessment of blood-cell-associated inflammatory markers may present a pragmatic and advantageous approach to the clinical oversight and therapeutic intervention of SCD. Key messages: What is known • Due to inflammation and local hypoxia, sickle-shaped red blood cells adhere to capillary endothelial cells. • This leads to decreased vascular flow, vaso-occlusion and microvascular complications. What is new • Sickle cell patients have increased inflammatory biomarkers compared to healthy. • Inflammatory biomarkers are increased in sickle cell retinopathy compared to without retinopathy. • SIMI and AISI are increased in proliferative sickle cell retinopathy. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Background: The CHOICES intervention is tailored specifically for young adults with sickle cell disease (SCD) or sickle cell trait (SCT). The face-to-face (F2F) delivery format is feasible with efficacy for improving knowledge about reproductive health for those with SCD or SCT. Purpose: The purpose of the study was to compare the participant adherence to a remote online CHOICES intervention study (N = 107) and a F2F CHOICES intervention study (N = 234). Methodology: In both studies, participants with SCD or SCT were randomized into experimental or usual care control groups. Descriptive statistics were collected for all participants by group in both studies. Adherence was measured by retention at each data collection time point. Independent t -tests were conducted to compare mean participant adherence of the F2F and online studies postbaseline (6, 12, 18, and 24 months). Results: There was a significant difference in mean adherence postbaseline between the studies (p =.005). The results suggest that more research is necessary for proper online participant retention. Conclusion: Advance practice nurses that are well informed on CHOICES can transmit the availability of this evidence-based intervention to this special population. Special referral for the CHOICES intervention, which is tailored specifically for young adults with SCD or SCT, may increase adherence to the intervention if it comes from trusted health care providers. Implications: Nurse practitioners are educators in primary and acute care settings. Encounters with reproductive age populations with SCD or SCT can occur in both settings. [ABSTRACT FROM AUTHOR]

Infertility is a common issue that threatens couples worldwide. Infertility can result from the male or female partner alone, or both partners. It can be due to multiple factors related to the patient's overall health or lifestyle. Causes related to patient health can be systemic or related to gonadal dysfunction. One of the systematic causes can be hematological. The two most common hemoglobinopathies that are thought to cause infertility, especially male infertility, are sickle cell disease (SCD) and thalassemia major (TM). These two hemoglobinopathies cause male infertility through pathophysiological alterations. Specifically, they alter the oxygen carrying ability of red blood cells (RBCs), causing tissue hypoxia that affects the normal physiological process of spermatogenesis, eventually inducing infertility. Semen analyses and other systemic blood testing can be used to investigate male infertility. Both hemoglobinopathies can be helped by blood transfusions, which can then alleviate male infertility. This paper aims to explore the relationship between hemoglobinopathies (SCD and TM) and their role in contributing to male infertility, in addition to the role of blood transfusions in addressing male infertility by correcting the root cause. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion Sickle cell disease (SCD) is associated with complications during pregnancy and can negatively influence maternal outcomes. Our study aimed to determine the prevalence and predictors of maternal morbidity among participants enrolled in an eight‐site SCD Implementation Consortium (SCDIC) registry.We conducted a cross‐sectional analysis of female registry participants, aged 15–45 years, with a confirmed diagnosis of SCD. Participants completed a survey of self‐reported pregnancies and outcomes.Seven hundred and thirty‐eight individuals had at least one pregnancy event, with 1076 live births. Twenty percent reported a pregnancy loss or fetal demise. Of the 1076 live births, 75% involved at least one complication. The most prevalent complications were pain crises (61.1%) and pregnancy requiring blood transfusion(s) (33.0%).Multiparous individuals with a prior occurrence of a complication in a previous pregnancy had higher odds of recurrence of the same complication in subsequent pregnancies (i.e., previous acute crisis was associated with subsequent acute pain events odds ratio [OR]: 3.13; 95% confidence interval [CI]: 2.06–4.76) and prior transfusion requiring another transfusion (OR: 3.22; 95% CI: 2.01–5.16).Individuals reported a high prevalence of pregnancy loss and maternal complications. Our findings underscore the importance of preconception counseling and early initiation of perinatal care in SCD. [ABSTRACT FROM AUTHOR]

Background: Sickle cell disease (SCD) is a genetic blood disorder characterized by a painful vaso-occlusive crisis due to the sickling of red blood cells in capillaries. Complications often lead to liver and renal dysfunctions, contributing to morbidity and mortality, particularly for children under 5. This systematic review and meta-analysis aimed to evaluate the liver and renal functions of people with SCD (HbSS) compared to those without it (HbAA) in Africa. Methods: The protocol was registered with PROSPERO (CRD42022346771). We searched PubMed, Embase, Web of Science, and Google Scholar using the keywords "liver function", "renal function", "sickle cell disease", and "Africa" on 6th May 2023 for peer-reviewed articles with abstracts in English. We included case-control studies comparing SCD (HbSS) with controls without hemoglobinopathies (HbAA). We used the random-effect model to calculate the pooled average values for the blood tests of people with SCD in RStudio version 4.2.2. Results: Overall, 17 articles were analyzed from five African countries involving 1312 people with SCD and 1558 controls. The pooled mean difference of liver enzymes aspartate transaminase (AST) was 8.62 (95% CI − 2.99–20.23, I2 = 97.0%, p < 0.01), alanine transaminase (ALT) 7.82 (95% CI − 0.16–15.80, I2 = 99%, p < 0.01) and alkaline phosphatase (ALP) − 2.54 (95% CI − 64.72 – 59.64, I2 = 99%, p < 0.01) compared to controls. The pooled mean difference for the renal biochemical profiles creatinine − 3.15 (95% CI − 15.02; 8.72, I2=99%, p < 0.01) with a funnel plot asymmetry of t = 1.09, df = 9, p = 0.3048 and sample estimates bias of 6.0409. The pooled mean difference for serum urea was − 0.57 (95% CI − 3.49; 2.36, I2 = 99%, p < 0.01), and the estimated glomerular filtration (eGFR) rate was 19.79 (95% CI 10.89–28.68 mL/min/1.73 m2, I2 = 87%, p < 0.01) compared to controls. Conclusion: People with SCD have slightly elevated liver enzymes and estimated glomerular filtration rates compared to controls in Africa. With all the heterogeneity (I2) > 50%, there was substantial variation in the reported articles' results. Systematic review registration: PROSPERO CRD42022346771 [ABSTRACT FROM AUTHOR]

Purpose: To investigate the phytochemical content and toxicity profile of Rauwolfia vomitoria Afze (Apocynaceae). Method: Qualitative phytochemical screening of hydro-alcohol extract (HAE) of R. vomitoria roots was carried out followed by acute toxicity evaluation in nine Swiss albino Wistar rats using two phases of Lorke's method. In the 14 days subacute study, thirty-two Swiss albino rats were randomly divided into 4 groups of 8 rats each. Group A received 0.5 mL Tween 80 daily and served as control, while groups B, C and D was administered 125, 250 and 500 mg/kg/day of HAE respectively. All the rats were monitored daily for signs of toxicity. Selected haematological and biochemical parameters were assessed at the termination of experiment. Results: Alkaloids, cardiac glycosides, flavonoids and saponins were present in HAE. The estimated oral median lethal dose (LD50) was greater than 5000 mg/kg. Daily administration of HAE for 14 days resulted in 15.63 % mortality of animals across the groups by day 14 with significant loss in total body weight in group D animals on day 8 (p < 0.05), and in group C animals on day 11 (p < 0.05) and day 15 (p < 0.001). The dose of 500 mg/kg/day significantly (p < 0.05) increased haemoglobin concentration but reduced (p < 0.05) white blood cell count, while the dose of 250 mg/kg/day significantly (p < 0.05) reduced alkaline phosphatase levels but increased serum albumin levels (p < 0.05). Conclusion: Rauwolfia vomitoria may be safe on acute basis but repeated administration of high doses over many days needs to be done with caution. [ABSTRACT FROM AUTHOR]

Patients with sickle cell disease (SCD) in Germany exhibit a substantial genetic diversity in the β‐globin genotype. Data collected by the national German SCD registry reflect this diversity and allowed us to analyze the phenotypes associated with different SCD genotypes. Our study focused on 90 patients with HbS/β‐thalassaemia (HbS/β‐thal) and compared these to patients with HbSS and HbSC. Patients with HbS/β‐thal were classified into three groups: HbS/β0‐thal (no HbA), HbS/β+‐thal (HbA < 14%), and HbS/β++‐thal (HbA≥14%). In comparison to HbSS, patients with HbS/β++‐thal had higher Hb‐levels, lower hemolytic activity and rarely required red blood cell transfusions. HbS/β0‐thal and HbS/β+‐thal closely resembled each other and are jointly referred to as HbS/β0/+‐thal. Compared to HbSS, patients with HbS/β0/+‐thal experienced a similar frequency of vasoocclusive crises and degree of hemolysis. However, the frequency of red blood cell transfusions (0.6 vs. 0.39/year, p =.0049) and splenic sequestration crises (42.4 vs. 15.5% of patients, p = 3.799e‐05) was higher in HbS/β0/+‐thal than in HbSS, but close to zero in HbS/β++‐thal. In conclusion, the level of HbA expression determines the phenotype of HbS/β+‐thal. HbS/β‐thal expressing no or little HbA is hematologically similar to HbSS, but causes a previously unknown high risk of splenic sequestration. [ABSTRACT FROM AUTHOR]

The US National Pain Strategy recommends identifying individuals with chronic pain (CP) who experience substantial restriction in work, social, or self-care activities as having high-impact chronic pain (HICP). High-impact chronic pain has not been examined among individuals with CP and sickle cell disease (SCD). We analyzed data from 63 individuals with SCD and CP who completed at least 5 months of pain diaries in the Pain in Sickle Cell Epidemiology Study (PiSCES). Forty-eight individuals met the definition for HICP, which was operationalized in this study as reporting pain interference on more than half of diary days. Compared with individuals without HICP, individuals with HICP experienced higher mean daily pain intensity, particularly on days without crises. They also experienced a greater proportion of days with pain, days with healthcare utilization, and days with home opioid use and higher levels of stress. They did not have a statistically significantly higher proportion of days with crises or experience higher mean daily pain intensity on days with crises. Individuals with HICP experienced worse physical functioning and worse physical health compared with those without HICP, controlling for mean pain intensity, age, sex, and education. The results of this study support that HICP is a severely affected subgroup of those with CP in SCD and is associated with greater pain burden and worse health outcomes. The findings from this study should be confirmed prospectively in a contemporary cohort of individuals with SCD. [ABSTRACT FROM AUTHOR]

Abstract Background Sickle cell disease (SCD) is a genetic blood disorder characterized by a painful vaso-occlusive crisis due to the sickling of red blood cells in capillaries. Complications often lead to liver and renal dysfunctions, contributing to morbidity and mortality, particularly for children under 5. This systematic review and meta-analysis aimed to evaluate the liver and renal functions of people with SCD (HbSS) compared to those without it (HbAA) in Africa. Methods The protocol was registered with PROSPERO (CRD42022346771). We searched PubMed, Embase, Web of Science, and Google Scholar using the keywords “liver function”, “renal function”, “sickle cell disease”, and “Africa” on 6th May 2023 for peer-reviewed articles with abstracts in English. We included case-control studies comparing SCD (HbSS) with controls without hemoglobinopathies (HbAA). We used the random-effect model to calculate the pooled average values for the blood tests of people with SCD in RStudio version 4.2.2. Results Overall, 17 articles were analyzed from five African countries involving 1312 people with SCD and 1558 controls. The pooled mean difference of liver enzymes aspartate transaminase (AST) was 8.62 (95% CI − 2.99–20.23, I 2 = 97.0%, p 50%, there was substantial variation in the reported articles’ results. Systematic review registration PROSPERO CRD42022346771

Hydroxyurea reduces sickle cell disease (SCD) complications, but medication adherence is low. We tested 2 mobile health (mHealth) interventions targeting determinants of low adherence among patients (InCharge Health) and low prescribing among providers (HU Toolbox) in a multi-center, non-randomized trial of individuals with SCD ages 15-45. We compared the percentage of days covered (PDC), labs, healthcare utilization, and self-reported pain over 24 weeks of intervention and 12 weeks post-study with a 24-week preintervention interval. We enrolled 293 patients (51% male; median age 27.5 years, 86.8% HbSS/HbSβ0-thalassemia). The mean change in PDC among 235 evaluable subjects increased (39.7% to 56.0%; P < 0.001) and sustained (39.7% to 51.4%, P < 0.001). Mean HbF increased (10.95% to 12.78%; P = 0.03). Self-reported pain frequency reduced (3.54 to 3.35 events/year; P = 0.041). InCharge Health was used ≥1 day by 199 of 235 participants (84.7% implementation; median usage: 17% study days; IQR: 4.8-45.8%). For individuals with ≥1 baseline admission for pain, admissions per 24 weeks declined from baseline through 24 weeks (1.97 to 1.48 events/patient, P = 0.0045) and weeks 25-36 (1.25 events/patient, P = 0.0015). PDC increased with app use (P < 0.001), with the greatest effect in those with private insurance (P = 0.0078), older subjects (P = 0.033), and those with lower pain interference (P = 0.0012). Of the 89 providers (49 hematologists, 36 advanced care providers, 4 unreported), only 11.2% used HU Toolbox ≥1/month on average. This use did not affect change in PDC. Tailoring mHealth solutions to address barriers to hydroxyurea adherence can potentially improve adherence and provide clinical benefits. A definitive randomized study is warranted. This trial was registered at www.clinicaltrials.gov as #NCT04080167.

Objectives: To determine the causes of hospitalization and outcome of children with sickle cell disorders at the University College Hospital, Ibadan. Methods: Case files of patients with sickle cell disease who were admitted between March 2009 and February 2012 were analysed. Data extracted include demographic variables, diagnoses, types of crises, associated infections, complications and outcome of treatment. Results: There were 174 admissions of 161 children with a male female ratio of 1.3:1. Their ages ranged from nine months to 18 years with a mean of 7.3(4.0) years. Vasoocclusive crisis was present in 107 (61.5%), hyper haemolytic crisis in 29 (16.7%) and acute splenic sequestration in 12 (6.9 %) of all admissions. Associated infections were septicaemia in 56 (32.2 %), malaria in 49 (28.2 %), acute osteomyelitis in 24 (13.8%), pneumonia in 23 (13.2%), urinary tract infection in 12 (6.9%) and septic arthritis in 10 (5.7%). Haematocrit was less than 15 % in 36 (20.7%) and blood transfusion administered in 68 (39.1%) of admissions. There were three (1.7%) deaths from cerebrovascular accident, adverse reaction to blood transfusion and meningitis. Conclusion: Prevention and prompt management of crises and infections in sickle cell disease is recommended to reduce morbidity and mortality.

Abstract If a mutated gene with heterozygous advantage against malaria, e.g., hemoglobin S (HbS) gene, is introduced in a small tribe, the gene (allele) frequency (f gene ) increases until it reaches a steady state value (f eq ) where the total mortality from malaria and sickle cell disease is a minimum. This is a classic example of balanced-polymorphism named malaria hypothesis. In a previous in silico study, assuming realistic initial conditions, it has been shown that the f eq is around 14%, far less than the f gene observed in certain parts of Africa, 24%. It seems that the malaria hypothesis, per se, could not explain such a high f gene , unless it is assumed that malaria and HbS gene can provide protection against other diseases. Using Monte-Carlo simulation, the current study was conducted to examine the effect on f eq of five scenarios was examined. The studied scenarios consisted of different combinations of mortality of other diseases and the possible amounts of protections conferred by malaria and HbS gene against the diseases. Taking into account other diseases causing mortality in the population makes the f gene rate of change steeper over generations. f eq is an increasing function of the amount of protection conferred by HbS gene against other diseases. The effect of protection provided by malaria against other diseases on f eq , is however, variable—depending on the amount of protection conferred by HbS gene against other diseases, it may increase or decrease f eq . If malaria and HbS gene provide protections of 1.5-fold and threefold against other diseases, respectively, the f eq is around 24%, the amount reported in certain tribes of Africa. Under certain scenarios, the f eq attained is even higher.

Purpose: Hydroxyurea (HU) is a cytoreductive agent used as standard treatment option for sickle cell anaemia/disease (SCD), essential thrombocythemia (ET), and polycythaemia vera (PV). Despite its overall good safety profile, its use also in relatively young patients raises an interest on its potential impact on spermatogenesis. To perform a systematic review of all published articles investigating fertility in male patients affected by SCD, ET, and PV and treated with HU. Two paradigmatic case reports of patients affected by PV and ET, respectively, have been also reported. Materials and Methods: PubMed, EMBASE, and Cochrane databases were queried for all the published studies indexed up to November 15th, 2022. A combination of the following keywords was used: “hydroxyurea,” “fertility,” “male,” “sperm,” “sickle cell anaemia,” “sickle cell disease,” “essential thrombocythemia,” “polycythaemia vera.” Results: Of 48 articles identified, 8 studies, involving 161 patients, were eligible for inclusion. Overall, the number of spermatogonia per round cross section of seminiferous tubule were decreased in patients with SCD compared to healthy males. HU treatment was always associated with a worsening of semen parameters, even up to azoospermia. Notably, treatment discontinuation was associated with an improvement of semen parameters and a trend toward normalization in the case of PV and ET, with a less clear amelioration in men with SCD. In both our patients with either PV or ET, HU discontinuation was associated with a significant improvement of spermatogenesis with successful spontaneous pregnancies. Conclusions: Published evidence do not consistently report normalization of spermatogenesis after HU discontinuation in SCD cases. Conversely, the literature almost consistently reported an improvement of semen parameters at the discontinuation of HU therapy in PV and ET cases. Our real-life two cases confirmed those findings. The willing of fatherhood and the need for effective fertility treatment warrant further research to improve work-up management in men with hematological disorders.

Summary Avascular necrosis (AVN) is a prevalent and progressive complication in young patients with sickle cell disease (SCD), but no study evaluated the long‐term subjective and objective outcome measures. Oxford hip score (OHS) and Oxford shoulder scores (OSS) are validated joint‐specific patient‐reported outcome measures (PROMs). In this prospective multicentre study, 47 SCD patients with pre‐existing diagnosis of AVN occurred at a median age of 35.9 (24.2–47.6) filled out the OHS and OSS at median follow‐up of 9.4 years (4.5–12.9). No patient died after diagnosis of AVN. Hip AVN was present in 34 (72%) patients, with bilateral involvement in 25 (74%); 26 (59%) underwent total hip arthroplasty (THA) at a median age of 34.6 (22.6–49.5); and 4 (15%) required re‐surgery. OHS revealed moderate to severe impairment both in patients underwent THA and no hip surgery. Shoulder AVN was present in 13 (6%) patients and OSS revealed mild to moderate impairment. A high rate of compromised joint function and pain was observed 10 years after diagnosis of AVN regardless of the type of treatment, outlying the need to improve the management of this sickle‐related complication. OHS and OSS are validated joint‐specific PROMs easy to use in all SCD centres. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is a hereditary haemoglobinopathy which causes multi‐organ dysfunction. Pregnancies in SCD are high risk with significant maternal and fetal morbidity and mortality, including vaso‐occlusive crises, thrombosis, anaemia, placental insufficiency, fetal growth restriction, preterm birth and medication effects. High level evidence on this topic is lacking. The Australian Sickle Cell Disease Working Group has reviewed international guidelines on this topic and provide an up‐to‐date and structured approach to the pre‐conception, antenatal, birth and post‐partum management of these women. Early and comprehensive multidisciplinary care involving experienced clinicians is recommended. [ABSTRACT FROM AUTHOR]

Some plants used in traditional medicine to manage sickle cell disease have been validated pharmacologically to ascertain their anti-sickling properties. However, there is no global systematic review of the evidence in support of their use for sickle cell management. This research aimed to conduct a systematic review of the pharmacological evidence to highlight species, genera, and some phytochemicals which could be primed for novel anti-sickling medications. The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines were used. Articles in English, published from 2000 to 2022 were included in the analysis. The literature search covered 411 publications of which 82 were found to be eligible. More than half (53.65%) of the articles were published from 2016 to 2022. Anti-sickling research from Africa accounted for 86.58% of the publications, with more than half coming from Nigeria, 12.20% from Asia and only 1.22% from Europe. The Fabaceae, Euphorbiaceae, and Annonaceae were the top three plant families whereas Zanthoxylum and Terminalia were the most reported genera. Carica papaya and Terminalia catappa were the most reported species. Sickling reversal (n = 33/82) and hemoglobin polymerization studies (n = 29/82) were the most reported assays. Benzoic acid derivatives, butyl stearate, ellagic acid derivatives, and some pentacyclic triterpenoids were the only plant derived compounds validated for anti-sickling activities. A total of 117 plant species with anti-sickling activities were documented. Studies on secondary metabolites with anti-sickling properties to serve as scaffolds for novel drug development for sickle cell management were limited. [ABSTRACT FROM AUTHOR]

Objectives: Sickle cell disease (SCD) is an inherited disorder that causes lifelong complications, substantially impacting the physical and emotional well‐being of patients and their caregivers. Studies investigating the effects of SCD on quality of life (QOL) are often limited to individual countries, lack SCD‐specific QOL questionnaires, and exclude the caregiver experience. The SHAPE survey aimed to broaden the understanding of the global burden of SCD on patients and their caregivers and to capture the viewpoint of healthcare providers (HCPs). Methods: A total of 919 patients, 207 caregivers, and 219 HCPs from 10, 9, and 8 countries, respectively, answered a series of closed‐ended questions about their experiences with SCD. Results: The symptoms most frequently reported by patients were fatigue/tiredness (84%) and pain/vaso‐occlusive crises (71%). Patients' fatigue/tiredness had one of the greatest impacts on both patients' and caregivers' QOL. On average, patients and caregivers reported missing 7.5 days and 5.0 days per month, respectively, of school or work. HCPs reported a need for effective tools to treat fatigue/tiredness and a desire for more support to educate patients on long‐term SCD‐related health risks. Conclusions: The multifaceted challenges identified using the SHAPE survey highlight the global need to improve both patient and caregiver QOL. [ABSTRACT FROM AUTHOR]

Purpose: In patients with a need for frequent but intermittent apheresis, vascular access can prove challenging. We describe the migration of the use of a Vortex LP dual lumen port (Angiodynamics, Latham, NY) to one Powerflow and one ClearVUE power injectable port (Becton Dickinson, Franklin Lakes, NJ) in a series of patients undergoing intermittent apheresis. Materials and Methods: All patients had a need for long‐term intermittent apheresis. Eight had double lumen Vortex port (pre) and were exchanged for one Powerflow port and one conventional subcutaneous venous port with 90° needle entry (post) while 12 did not have any port in place and received the same configuration. IRB approval was granted. We recorded the treatment time, flow rate, and tissue plasminogen activator (tPA) use for five treatment sessions after placement. When available, we compared five treatments with the Vortex port and the new configuration. Results: The mean treatment time is reduced with the new configuration (P = 0.0033). The predicted mean treatment time, adjusting for gender, race, BMI and age and accounting for correlations within a patient is 91.18 min pre and 77.96 min post. The flow rate is higher with the new configuration (P < 0.0001). The predicted mean flow rate in mL/min is 61.59 for the Vortex port and 71.89 for the new configuration. tPA use was eliminated in the population converted from Vortex ports and had a 48% reduction when compared to all other configurations in the study. Conclusion: The introduction of a novel device configuration of venous access ports for intermittent apheresis resulted in higher flow rates and less total time for treatment. Use of tPA was greatly reduced. These results suggest that the new configuration could result in less expense for the hospital and better throughput in a busy pheresis practice. Clinical trial registration with ClinicalTrials.gov: NCT04846374. [ABSTRACT FROM AUTHOR]

Introduction: Despite over 100 years of neglect and insufficient funding, sickle cell disease has risen to the top of the discussions due to the recent approval of two new genetic therapies. Prior to these approvals, there were only four prior approved medications for sickle cell disease in spite of being the most common inherited blood disorder. The advent and expense of these new genetic therapies have finally brought the trials and tribulations associated with SCD including the suffering and early mortality of affected individuals to the much-needed limelight. Presently, questions about how these therapies will be used and what that means for ongoing pharmaceutical development remain. Areas covered: Here, we wish to highlight the current medications and treatments for SCD using already published literature as well as scrutinize the tedious process of implementation for these newly approved commercial genetic therapies. Expert opinion: In our expert opinion, despite the progress we have made, significant challenges remain and the most important requirement for any of these treatments is ensuring all affected individuals have access to a sickle cell specialist who can provide comprehensive care. [ABSTRACT FROM AUTHOR]

The pathophysiologic mechanism of sickle cell disease (SCD) involves polymerization of deoxygenated haemoglobin S (HbS), leading to red blood cell (RBC) sickling, decreased RBC deformability, microvascular obstruction, haemolysis, anaemia and downstream clinical complications. Pharmacological increase in the concentration of oxygenated HbS in RBCs has been shown to be a novel approach to inhibit HbS polymerization and reduce RBC sickling and haemolysis. We report that GBT021601, a small molecule that increases HbS-oxygen affinity, inhibits HbS polymerization and prevents RBC sickling in blood from patients with SCD. Moreover, in a murine model of SCD (SS mice), GBT021601 reduces RBC sickling, improves RBC deformability, prolongs RBC half-life and restores haemoglobin levels to the normal range, while improving oxygen delivery and increasing tolerance to severe hypoxia. Notably, oral dosing of GBT021601 in animals results in higher levels of Hb occupancy than voxelotor and suggests the feasibility of once-daily dosing in humans. In summary, GBT021601 improves RBC health and normalizes haemoglobin in SS mice, suggesting that it may be useful for the treatment of SCD. These data are being used as a foundation for clinical research and development of GBT021601.

BackgroundCOVID-19, the pandemic that hit the world in 2020, resulted in millions of deaths, with the elderly and adults succumbing to the disease more often than children. However, the presence of underlying morbidities increased the risk of death. Sickle cell disease (SCD) was previously classified as a major risk factor for severe COVID-19 disease. However, presently, there are only a limited number of studies that identify the clinical course of children with SCD and COVID-19.MethodsWe conducted a retrospective observational study on children with SCD admitted due to COVID-19 at three different institutions in Saudi Arabia between March 2020 and March 2022. We studied the demographic and clinical characteristics of patients admitted to the hospital.ResultsSeventy-six patients with SCD had PCR-confirmed SARS-CoV-2 during the study period; 50.0% of our patient population were children (6–12 years old). Gender was evenly distributed, with 53.9% girls and 46.1% boys. Symptoms more commonly related to the COVID-19 infection included fever, cough, malaise, and vomiting. Chest x-ray findings revealed mild and non-specific symptoms only in approximately one-third (28) of the included children. The most common symptoms associated with SCD were vaso-occlusive crisis (47.4%) and abdominal pain (11.8%). The overall general appearance of most of the patients was reassuring. The median length of hospital stay was 4.2 ± 2.7 days. The mean white blood cell count was 11.4 ± 5.2 × 109/L, and the mean hemoglobin level was 8.3 ± 1.5 g/dl. Despite the fact that higher levels of mean D-dimer, lactate dehydrogenase, and ferritin were reported in these patients, the clinical outcome was not affected. All recruited patients received hydroxyurea as maintenance therapy. The outcome of our study was reassuring, with no significant morbidity or mortality observed among the recruited patients.ConclusionDespite SCD being a chronic disease with known specific complications, there has been a claim that COVID-19 infection adds further risk. The results of this study suggest that the overall outcome of COVID-19 was favorable, with no reported mortality. Further research is needed to understand the factors that contributed to this favorable outcome. In children with SCD, it is still questionable whether hydroxyurea is one of the protective factors against severe COVID-19. Validation through large-scale research is recommended.

Intravascular hemolysis results in the release of cell-free hemoglobin and heme in plasma. In sickle cell disease, the fragility of the sickle red blood cell leads to chronic hemolysis, which can contribute to oxidative damage and activation of inflammatory pathways. The scavenger proteins haptoglobin and hemopexin provide pathways to remove hemoglobin and heme, respectively, from the circulation. Heme also intercalates in membranes of blood cells and endothelial cells in the vasculature and associates with other plasma components such as albumin and lipoproteins. Hemopexin has a much higher affinity and can strip heme from the other pools and detoxify plasma from cell-free circulatory heme. However, due to chronic hemolysis, hemopexin is depleted in individuals with sickle cell disease. Thus, cell-free unbound heme is expected to accumulate in plasma. We developed a methodology for the accurate quantification of the fraction of heme, which is pathologically relevant in sickle cell disease, that does not appear to be sequestered to a plasma compartment. Our data show significant variation in the concentration of unbound heme, and rather unexpectedly, the size of the unbound fraction does not correlate to the degree of hemolysis, as measured by the concentration of bound heme. Very high heme concentrations (>150 µM) were obtained in some plasma with unbound concentrations that were several fold lower than in plasma with much lower hemolysis (

ImportancePain related to sickle cell disease (SCD) is complex and associated with social determinants of health. Emotional and stress-related effects of SCD impact daily quality of life and the frequency and severity of pain.ObjectiveTo explore the association of educational attainment, employment status, and mental health with pain episode frequency and severity among individuals with SCD.Design, setting, and participantsThis is a cross-sectional analysis of patient registry data collected at baseline (2017-2018) from patients treated at 8 sites of the US Sickle Cell Disease Implementation Consortium. Data analysis was performed from September 2020 to March 2022.Main outcomes and measuresElectronic medical record abstraction and a participant survey provided demographic data, mental health diagnosis, and Adult Sickle Cell Quality of Life Measurement Information System pain scores. Multivariable regression was used to examine the associations of education, employment, and mental health with the main outcomes (pain frequency and pain severity).ResultsThe study enrolled a total of 2264 participants aged 15 to 45 years (mean [SD] age, 27.9 [7.9] years; 1272 female participants [56.2%]) with SCD. Nearly one-half of the participant sample reported taking daily pain medication (1057 participants [47.0%]) and/or hydroxyurea use (1091 participants [49.2%]), 627 participants (28.0%) received regular blood transfusion, 457 (20.0%) had a depression diagnosis confirmed by medical record abstraction, 1789 (79.8%) reported severe pain (rated most recent pain crises as ≥7 out of 10), and 1078 (47.8%) reported more than 4 pain episodes in the prior 12 months. The mean (SD) pain frequency and severity t scores for the sample were 48.6 (11.4) and 50.3 (10.1), respectively. Educational attainment and income were not associated with increased pain frequency or severity. Unemployment (β, 2.13; 95% CI, 0.99 to 3.23; P

PURPOSE: To report the incidence and risk factors for secondary neoplasm after transplantation for sickle cell disease. METHODS: Included are 1,096 transplants for sickle cell disease between 1991 and 2016. There were 22 secondary neoplasms. Types included leukemia/myelodysplastic syndrome (MDS; n = 15) and solid tumor (n = 7). Fine-Gray regression models examined for risk factors for leukemia/MDS and any secondary neoplasm. RESULTS: The 10-year incidence of leukemia/MDS was 1.7% (95% CI, 0.90 to 2.9) and of any secondary neoplasm was 2.4% (95% CI, 1.4 to 3.8). After adjusting for other risk factors, risks for leukemia/MDS (hazard ratio, 22.69; 95% CI, 4.34 to 118.66; P = .0002) or any secondary neoplasm (hazard ratio, 7.78; 95% CI, 2.20 to 27.53; P = .0015) were higher with low-intensity (nonmyeloablative) regimens compared with more intense regimens. All low-intensity regimens included total-body irradiation (TBI 300 or 400 cGy with alemtuzumab, TBI 300 or 400 cGy with cyclophosphamide, TBI 200, 300, or 400 cGy with cyclophosphamide and fludarabine, or TBI 200 cGy with fludarabine). None of the patients receiving myeloablative and only 23% of those receiving reduced-intensity regimens received TBI. CONCLUSION: Low-intensity regimens rely on tolerance induction and establishment of mixed-donor chimerism. Persistence of host cells exposed to low-dose radiation triggering myeloid malignancy is one plausible etiology. Pre-existing myeloid mutations and prior inflammation may also contribute but could not be studied using our data source. Choosing conditioning regimens likely to result in full-donor chimerism may in part mitigate the higher risk for leukemia/MDS.

We previously conducted a single-arm feasibility study (STRIDE1) of myeloablative bone marrow transplantation (BMT) in adolescents and young adults with sickle cell disease (SCD). The trial identified donors before entry, enrolled well, and found no unexpected regimen-related toxicity. Although many single-arm studies have been published, there are no controlled trials of either BMT or gene therapy in SCD. Therefore, we designed a comparative trial by biological assignment (available donor versus no donor). This multicenter National Institutes of Health-funded study (Blood and Marrow Transplant Clinical Trials Network 1503; STRIDE2) enrolled patients between 2016 and 2021 at 35 sites. Lagging recruitment led to study closure, and here we report the impediments to accrual. The BMT regimen and entry criteria were from STRIDE1, and 2-year survival was the primary endpoint. To minimize selection bias from prior HLA typing, STRIDE2 excluded individuals with previously identified donors. Accrual was stopped at 69% of target (138 enrolled; assigned 28 with donor, 96 with no donor). Barriers to enrollment included lower than expected frequency of HLA-matched related and unrelated donors; loss of enrollees owing to previously identified donors; conventional care arm dissuading some seeking BMT; challenging short-term endpoints in SCD, including incomplete documentation of sickle pain episodes; state Medicaid (primary insurers of SCD) denial of BMT coverage for adult SCD despite the study having secured Coverage with Evidence Development from the Center for Medicare & Medicaid Services; slowed accrual in 2019 to 2021 during the Coronavirus disease 2019 pandemic; and restriction of BMT resourcing for nonmalignant diseases by academic medical (cancer) centers. Social obstacles and access to BMT centers also limited entry, as did practitioner and participant concerns over suitability, cost, and toxicity. Planning for future controlled trials of curative therapy in SCD and other nonmalignant diseases likely will meet these enrollment challenges. Lessons from this trial may aid the development of future comparative studies.

Ischaemic stroke is a common complication of sickle cell disease (SCD) and without intervention can affect 11% of children with SCD before the age of 20. Within the Trans-Omics for Precision Medicine (TOPMed), a genome-wide association study (GWAS) of ischaemic stroke was performed on 1333 individuals with SCD from Brazil (178 cases, 1155 controls). Via a novel Cox proportional-hazards analysis, we searched for variants associated with ischaemic stroke occurring at younger ages. Variants at genome-wide significance (p

Adverse pregnancy outcomes occur frequently in women with sickle cell disease (SCD) across the globe. In the United States, Black women experience disproportionately worse maternal health outcomes than all other racial groups. To better understand how social determinants of health impact SCD maternal morbidity, we used California's Department of Health Care Access and Information data (1991-2019) to estimate the cumulative incidence of pregnancy outcomes in Black women with and without SCD-adjusted for age, insurance status, and Distressed Community Index (DCI) scores. Black pregnant women with SCD were more likely to deliver at a younger age, use government insurance, and live in at-risk or distressed neighborhoods, compared to those without SCD. They also experienced higher stillbirths (26.8, 95% confidence interval [CI]: 17.5-36.1 vs. 12.4 [CI: 12.1-12.7], per 1000 births) and inpatient maternal mortality (344.5 [CI: 337.6-682.2] vs. 6.1 [CI: 2.3-8.4], per 100 000 live births). Multivariate logistic regression models showed Black pregnant women with SCD had significantly higher odds ratios (OR) for sepsis (OR 14.89, CI: 10.81, 20.52), venous thromboembolism (OR 13.60, CI: 9.16, 20.20), and postpartum hemorrhage (OR 2.25, CI 1.79-2.82), with peak onset in the second trimester, third trimester, and six weeks postpartum, respectively. Despite adjusting for sociodemographic factors, Black women with SCD still experienced significantly worse pregnancy outcomes than those without SCD. We need additional studies to determine if early introduction to reproductive health education, continuation of SCD-modifying therapies during pregnancy, and increasing access to multidisciplinary perinatal care can reduce morbidity in pregnant women with SCD.

Sickle cell disease (SCD) results from a single base pair change in the sixth codon of the β-globin chain of hemoglobin, which promotes aggregation of deoxyhemoglobin, increasing rigidity of red blood cells and causing vaso-occlusive and hemolytic complications. Allogeneic transplant of hematopoietic stem cells (HSCs) can eliminate SCD manifestations but is limited by absence of well-matched donors and immune complications. Gene therapy with transplantation of autologous HSCs that are gene-modified may provide similar benefits without the immune complications. Much progress has been made, and patients are realizing significant clinical improvements in multiple trials using different approaches with lentiviral vector-mediated gene addition to inhibit hemoglobin aggregation. Gene editing approaches are under development to provide additional therapeutic opportunities. Gene therapy for SCD has advanced from an attractive concept to clinical reality.

BackgroundThis study aimed to capture the implementation process of the ALIGN Study, (An individualized Pain Plan with Patient and Provider Access for Emergency Department care of Sickle Cell Disease). ALIGN aimed to embed Individualized Pain Plans in the electronic health record (E-IPP) and provide access to the plan for both adult patients with sickle cell disease (SCD) and emergency department providers when a person with SCD comes to the emergency department in vaso-occlusive crises.MethodsSemi-structured interviews were conducted with research teams from the 8 participating sites from the ALIGN study. Seventeen participants (principal investigators and study coordinators) shared their perspectives about the implementation of ALIGN in their sites. Data were analyzed in three phases using open coding steps adapted from grounded theory and qualitative content analysis.ResultsA total of seven overarching themes were identified: (1) the E-IPP structure (location and upkeep) and collaboration with the informatics team, (2) the role of ED champion, (3) the role of research coordinators, (4) research team communication, and communication between research team and clinical team, (5) challenges with the study protocol, (6) provider feedback: addressing over-utilizers, patient mistrust, and the positive feedback about the intervention, and (7) COVID-19 and its effects on study implementation.ConclusionsFindings from this study contribute to learning how to implement E-IPPs for adult patients with SCD in ED. The study findings highlight the importance of early engagement with different team members, a champion from the emergency department, study coordinators with different skills and enhancement of communication and trust among team members. Further recommendations are outlined for hospitals aiming to implement E-IPP for patients with SCD in ED.

Sickle cell disease is a monogenic hemoglobinopathy that results in the abnormal production of hemoglobin S, which yields the characteristic sickle-shaped red blood cells. Sickle cell vaso-occlusive crisis is a painful complication of sickle cell disease caused by red blood cell entrapment within the microcirculation. The resulting tissue ischemia triggers a secondary inflammatory process involved in the pathogenesis of varying inflammatory skin conditions. Chronic leg ulcers are the most common skin presentation in sickle cell disease. A 58-year-old woman with sickle cell disease presented with systemic edematous plaques with the most notable involvement of her bilateral legs, which exhibited reticulated purpuric patches with central pallor. We report a case highlighting an unusual presentation of livedo racemosa as the presenting sign in a patient with sickle cell disease in vaso-occlusive crisis.

Investigations to understand the function and control of the globin genes have led to some of the most exciting molecular discoveries and biomedical breakthroughs of the 20th and 21st centuries. Extensive characterization of the globin gene locus, accompanied by pioneering work on the utilization of viruses as human gene delivery tools in human hematopoietic stem and progenitor cells (HPSCs), has led to transformative and successful therapies via autologous hematopoietic stem-cell transplant with gene therapy (HSCT-GT). Due to the advanced understanding of the β-globin gene cluster, the first diseases considered for autologous HSCT-GT were two prevalent β-hemoglobinopathies: sickle cell disease and β-thalassemia, both affecting functional β-globin chains and leading to substantial morbidity. Both conditions are suitable for allogeneic HSCT; however, this therapy comes with serious risks and is most effective using an HLA-matched family donor (which is not available for most patients) to obtain optimal therapeutic and safe benefits. Transplants from unrelated or haplo-identical donors carry higher risks, although they are progressively improving. Conversely, HSCT-GT utilizes the patient's own HSPCs, broadening access to more patients. Several gene therapy clinical trials have been reported to have achieved significant disease improvement, and more are underway. Based on the safety and the therapeutic success of autologous HSCT-GT, the U.S. Food and Drug Administration (FDA) in 2022 approved an HSCT-GT for β-thalassemia (Zynteglo™). This review illuminates the β-globin gene research journey, adversities faced, and achievements reached; it highlights important molecular and genetic findings of the β-globin locus, describes the predominant globin vectors, and concludes by describing promising results from clinical trials for both sickle cell disease and β-thalassemia.

lovo-cel (bb1111; LentiGlobin for sickle cell disease [SCD]) gene therapy (GT) comprises autologous transplantation of hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified β-globin gene (βA-T87Q ) to produce anti-sickling hemoglobin (HbAT87Q ). The efficacy and safety of lovo-cel for SCD are being evaluated in the ongoing phase 1/2 HGB-206 study (ClinicalTrials.gov: NCT02140554). The treatment process evolved over time, using learnings from outcomes in the initial patients to optimize lovo-cel's benefit-risk profile. Following modest expression of HbAT87Q in the initial patients (Group A, n = 7), alterations were made to the treatment process for patients subsequently enrolled in Group B (n = 2, patients B1 and B2), including improvements to cell collection and lovo-cel manufacturing. After 6 months, median Group A peripheral blood vector copy number (≥0.08 c/dg) and HbAT87Q levels (≥0.46 g/dL) were inadequate for substantial clinical effect but stable and sustained over 5.5 years; both markedly improved in Group B (patient B1: ≥0.53 c/dg and ≥2.69 g/dL; patient B2: ≥2.14 c/dg and ≥6.40 g/dL, respectively) and generated improved biologic and clinical efficacy in Group B, including higher total hemoglobin and decreased hemolysis. The safety of the lovo-cel for SCD treatment regimen largely reflected the known side effects of HSPC collection, busulfan conditioning regimen, and underlying SCD; acute myeloid leukemia was observed in two patients in Group A and deemed unlikely related to insertional oncogenesis. Changes made during development of the lovo-cel treatment process were associated with improved outcomes and provide lessons for future SCD GT studies.

The utilizations of microfluidic chips for single RBC (red blood cell) studies have attracted great interests in recent years to filter, trap, analyze, and release single erythrocytes for various applications. Researchers in this field have highlighted the vast potential in developing micro devices for industrial and academia usages, including lab-on-a-chip and organ-on-a-chip systems. This article critically reviews the current state-of-the-art and recent advances of microfluidics for single RBC analyses, including integrated sensors and microfluidic platforms for microscopic/tomographic/spectroscopic single RBC analyses, trapping arrays (including bifurcating channels), dielectrophoretic and agglutination/aggregation studies, as well as clinical implications covering cancer, sepsis, prenatal, and Sickle Cell diseases. Microfluidics based RBC microarrays, sorting/counting and trapping techniques (including acoustic, dielectrophoretic, hydrodynamic, magnetic, and optical techniques) are also reviewed. Lastly, organs on chips, multi-organ chips, and drug discovery involving single RBC are described. The limitations and drawbacks of each technology are addressed and future prospects are discussed.

Background: Pain is the prominent feature of sickle cell disease (SCD) and negatively affects quality of life. Delivery of pain management programmes (PMPs) has been suggested in clinical guidelines for pain management in SCD; however, further evidence of the feasibility and effectiveness of PMPs in this population is needed. This study explored the feasibility of delivering a sickle cell pain management programme (SCPMP) for adults within a haemoglobinopathies service. Methods: A single arm, repeated-measures observational design was used to determine feasibility of delivering the SCPMP at one study site. Primary feasibility outcomes were recruitment, completion of treatment and outcome measures, satisfaction, credibility and acceptability to participants. Secondary feasibility outcomes were treatment outcomes and processes, frequency of vaso-occlusive crisis (VOC) and healthcare utilisation. Results: Four of five feasibility criteria were met. Annual recruitment of eight participants to a SCPMP was not achieved. Twenty-nine people began a SCPMP during the study period. Twenty-five (86.2%) participants attended ≥5/8 sessions and 21(84%) programme completers provided all end of programme questionnaires. Mean scores of >7 on ten-point scales were seen across satisfaction and credibility questions. At least moderate (Hedges g >0.5) effect sizes were seen in pre-post SCPMP measures of pain interference, anxiety, depression, self-efficacy, pain-related worry and acceptance. A small (Hedges g 0.4) effect size was seen in HRQoL. Following SCPMP attendance, mean frequency of self-reported VOC and hospital admissions reduced. Conclusions: This study suggests that, given an adequate source of referrals, a SCPMP is feasible to deliver and appears acceptable and credible to participants. Exploration of influences on recruitment, such as barriers to group interventions, would be illuminating, prior to investigating feasibility of an adequately powered randomised-controlled trial. [ABSTRACT FROM AUTHOR]

Iron deficiency anaemia (IDA) is unusual in sickle cell disease (SCD). However, excessive urinary iron loss and mucosal/submucosal infarcts may result in poor absorption of iron in SCD. During the first decade of the disease, environmental factors and poor nutrition may also affect iron metabolism and contribute to iron deficiency in SCD. The present study assessed iron status and haematological profile of young children with SCD using serum Iron, Ferritin and Total Iron Binding Capacity (TIBC) to establish early diagnosis of IDA.Results showed that out of 6276 newborns screened, 33(0.52%) were detected to have SCD. Amongst 33,14(14.28%) children were suspected to have IDA. Iron studies revealed 42.4% of coexistent IDA with low serum Iron among 3 children, whereas high normal or raised TIBC was seen in 14 children. The findings emphasize that raised TIBC with normal serum iron may indicate early onset of IDA in the early decade of SCD, highlighting the need of timely initiation of iron therapy to prevent further severe events. [ABSTRACT FROM AUTHOR]

Why you should read this article: • To understand why vaso-occlusive crises in sickle cell disease should be treated as a medical emergency • To increase your awareness of why patients with sickle cell disease often receive suboptimal care • To acknowledge the need for staff education on sickle cell disease so that patients receive appropriate care. Most patients with sickle cell disease (SCD) need support from healthcare services to manage their condition, including painful vaso-occlusive crises. Vaso-occlusive crises should be treated as a medical emergency, but the quality of the care patients receive when they present to the emergency department (ED) is often suboptimal. This article reports the findings of a literature review on the views of ED nurses and doctors about patients with SCD. The review included four studies, all of which had been conducted in the US, demonstrating that research on the topic is limited. The review found mostly negative views, including the belief that patients misuse pain medicines and demonstrate drug-seeking behaviours. Racial bias, widely recognised as a negative influence on the care of patients with SCD, was not mentioned in any of the studies. Staff education regarding SCD is required to ensure patients receive the care they need when they present to the ED. [ABSTRACT FROM AUTHOR]

Introduction: Sickle-cell anaemia is a hereditary disorder characterised by the presence of sickle-cell haemoglobin genes acquired from both parents. Sodium (Na+), potassium (K+), and chloride (Cl-) are indispensable electrolytes that play a crucial role in facilitating the proper functioning of cells and organs. The current investigation was conducted to assess and establish the correlation between electrolyte levels in individuals diagnosed with Sickle cell anaemia. Objective: To assess the relative amounts of serum electrolytes in the Sickle cell group compared to the control group. Method: A metaanalysis was conducted on the results of 10 published research pertaining to the serum electrolyte levels of individuals diagnosed with sickle cell anaemia. A random-effects model was employed to determine the pooled mean for serum electrolytes. Results: The combined average of serum sodium levels was lower in individuals with sickle cell anaemia, with a p-value of 0.04. Nevertheless, the potassium levels in patients were significantly elevated compared to controls, with a p-value of 0.01. Conclusion: The utilisation of pooled mean, as presented in this study, holds potential value in the formulation of strategies for managing sickle cell anaemia. [ABSTRACT FROM AUTHOR]

Objective: To identify the educational technologies used to help children with sickle cell anemia in their self-care. Method: an integrative review carried out in six consecutive phases, between June and July 2023, with no time frame, in the following information resources: Public/published Medline, Virtual Health Library, Scientific Electronic Library Onl ine, and Web of Science and Cumulative Index to Nursing and Allied Health Literature. Results: Five studies were found, of which the following stood out: a game, two electronic applications, a coloring book, and a guided image for pain relief. All the educational technologies reflect the child's better understanding of self-care. Conclusion: The selected studies allowed us to understand that educational technologies help children with sickle cell anemia to understand the disease and take actions that improve its signs and symptoms, favoring self-care, but it is essential to create new educational technologies since most of the findings are old and do not match the current reality.

People with sickle cell disease experience a high incidence of chronic kidney disease and end-stage kidney disease, secondary to tubular and glomerular effects of vaso-occlusion-induced hypoxia. Because of concerns of suboptimal kidney function, sickle cell donors are usually not considered for kidney donation, even if the rest of the parameters are acceptable for organ donation. A significant gap exists between the number of organ donors and the number of candidates waiting for a kidney transplant in the United States. To bridge the gap, we need to consider using nontraditional donors. We report kidney transplant outcomes in 6 recipients from 4 sickle cell kidney donors. Intracranial hemorrhage and sepsis were the causes of the death in donors, and no donor was in sickle cell crisis at the time of donation. None of the recipients experienced delayed graft function, and all recipients achieved excellent allograft function. The earliest allograft failure was at 27 months in a recipient who developed early acute rejection, while the longest follow-up was 10 years with adequate kidney function. In conclusion, given the shortage of kidneys for transplantation and demonstrated good outcomes, we propose that kidneys from sickle cell donors can be safely used.

BACKGROUND AND OBJECTIVES: Sickle cell disease is considered the most common hereditary disorder in Brazil. The chronic pain resulting from some complications of sickle cell disease is still poorly understood, inadequately described, and under-researched. This study aimed to characterize chronic pain in individuals with sickle cell disease, evaluate its treatment, and discuss the importance of studying it as a distinct pathology. METHODS: A cross-sectional study based on comparative analysis between two associations of sickle cell disease patients, one in Brazil and the other in France. The Pain Detect Questionnaire was used to assess neuropathic pain, and Odds Ratio was used to evaluate the strength of the association between opioid use and the recurrence of chronic painful crises. RESULTS: In Brazil, the Pain Detect questionnaire revealed that 55% of patients had a probable neuropathic component, 23% negative, and 22% uncertain. In France, the application resulted in 51% for probable presence, 29% for negative, and 20% for uncertain. All patients reported constant pain. As for the frequent use of opioids, the results were 62% in Brazil and 32% in France. The Odds Ratio calculation results were: OR 15.14 (95% CI = 4.777- 41.4, p < 0.0001) in Brazil; and OR 7.5 (95% CI = 2.121- 25.74, p = 0.0013) in France. CONCLUSION: While it is commonly believed that pain in sickle cell disease is primarily related to somatic and visceral tissue damage after vaso-occlusive events, this study indicated emerging evidence of neuropathic processes involved. Thus, there should be a significant concern about the management of chronic pain and particularly opioid dependence in Brazil.

Curative therapies for sickle cell disease (SCD) include allogeneic human leukocyte antigen (HLA)- matched sibling and haploidentical hematopoietic cell transplant (HCT), gene therapy, and gene editing. However, comparative trial data that might facilitate selecting one curative therapy over another are unavailable. New strategies to decrease graft rejection and graft-versus-host disease (GVHD) risks are needed to expand haploidentical HCT. Myeloablative gene therapy and gene editing also has limitations. Herein, we review recent studies on curative therapies for SCD in the past 5 years.

Manifestations of sickle cell disease (SCD) begin early in childhood and cause morbidity and decreased life expectancy. Hematopoietic stem cell transplantation (HSCT) is curative but associated with risk of mortality attributable to the transplant. This risk should be counterbalanced with SCD morbidity and mortality. A severity score using a Bayesian network model was previously validated to predict the risk of death in adult individuals with SCD. The objective of this study is to calculate the severity scores of participants in a multicenter cohort of Brazilians with SCD, using a previously published Bayesian network-derived score, associated with risk of death and then compare the severity scores between participants with and without an indication for HSCT as defined by the Brazilian Ministry of Health (MoH) criteria. This is an observational, retrospective study. We analyzed 2063 individuals with sickle cell anemia from the Recipient Epidemiology and Donor Evaluation Study-III Brazil SCD cohort and applied a Bayesian network-derived score to compare candidates and non-candidates for HSCT according to the Brazilian MoH transplant criteria. Classical statistical methods were used to analyze data and make comparisons. We compared severity scores between cohort members with (n = 431) and without (n = 1632) HSCT indications according to Brazilian MoH. Scores were not different in adult participants with ≥1 HSCT indication when compared to those with no indication (mean 0.342 versus 0.292; median 0.194 versus 0.183, P = .354) and receiver operating characteristic curves did not demonstrate an obvious threshold to differentiate participants with or without HSCT indications. Severity score may predict risk of death but does not differentiate HSCT candidates. Current indications should be evaluated to ensure that patients with more severe disease who might benefit from HSCT are appropriately identified.