Search Results (721)

Sickle cell anemia (SCA) is a genetic disorder characterized by chronic hemolysis, primarily driven by red blood cell lysis. Its pathophysiology is centered, though not exclusively, on the increased release of intracellular components, such as hemoglobin degradation products, which are known to stimulate innate immune responses and promote prothrombotic states. Current therapies alleviate symptoms, yet patients remain exposed to a chronic inflammatory milieu punctuated by episodes of acute pain. The recurrence of these crises can be life-threatening due to ischemia–reperfusion injury, hypercoagulability, and respiratory complications. Central mechanisms are marked by elevated hemolysis, heightened inflammatory signaling, and increased procoagulant activity, largely driven by soluble molecules released into the plasma, such as hemoglobin, nuclear molecules and other products. These compounds are recognized from sensors on immune and endothelial cells, named Pattern Recognition Receptors (PRRs), and constitute canonical pathways for intracellular activation. Four main types have been extensively studied in the literature over recent years in both infectious and sterile inflammatory contexts; still, only a few have elucidated the mechanisms underlying acute and chronic inflammation in patients with SCA. Although Toll receptors were shown to be major in triggering immunity, other receptors were found to be important regarding this function, which suggested a multifactorial mechanism for this triggering. Therefore, here, we propose a comprehensive review of previously published findings regarding the expression, activation, and dynamics of Toll-like, NOD-like, and RIG-I–like receptors in the progression of SCA and its associated inflammatory features. Full article

Background and Objectives: Pulmonary hypertension (PH) is a major contributor to morbidity and mortality in sickle cell disease (SCD), yet reliable and accessible biomarkers for cardiopulmonary risk stratification remain limited. This study aimed to evaluate whether the platelet-to-neutrophil ratio (PNR) is independently associated with echo-estimated PH (ePH) in adolescents and adults with SCD and to compare its predictive value with hemoglobin composition and genotype. Materials and Methods: A retrospective cohort study was conducted at King Fahd Hospital of the University, Al Khobar, Saudi Arabia (January 2019–January 2025). Clinical, laboratory, and echocardiographic data from 114 patients with confirmed SCD who underwent transthoracic echocardiography (TTE) were analyzed. ePH was defined as tricuspid regurgitant velocity (TRV) ≥ 2.5 m/s or pulmonary artery acceleration time (PAAT) ≤ 105 ms. Multivariable logistic and linear regression models were used to assess associations between PNR, hemoglobin fractions, genotype, and pulmonary pressure estimates. Results: Overall, 43% of patients met the criteria for ePH. PNR was not independently associated with ePH or TRV in adjusted analyses. In contrast, higher fetal hemoglobin (HbF) levels were independently associated with lower odds of ePH (adjusted OR 0.92 per 1% increase, 95% CI 0.86–0.98) and lower TRV values. The HbS/β⁰ genotype was significantly associated with increased odds of ePH (adjusted OR 5.44, 95% CI 1.37–24.0). Exploratory analyses demonstrated an inverse association between PNR and lactate dehydrogenase, suggesting that PNR reflects hemolytic activity rather than pulmonary vascular involvement. Conclusions: In this retrospective cohort of patients with SCD, PNR was not independently associated with ePH or TRV after multivariable adjustment. In contrast, hemoglobin composition and genotype, particularly higher HbF and the HbS/β⁰ genotype, were significantly associated with pulmonary pressure estimates. Full article

Sickle cell disease (SCD) is a major public health concern in Tanzania where approximately 11,000 children are born with the condition annually. Newborn screening (NBS) enables early diagnosis and timely intervention. Despite the proven effectiveness of NBS in reducing early mortality from SCD, implementation in Tanzania remains limited to pilot programs at facilities such as Temeke and Amana Regional Referral Hospitals (RRHs) in the city of Dar-es-salaam. This study evaluated the implementation of NBS for the SCD Program at Temeke and Amana RRHs. An explanatory mixed-methods process evaluation was conducted between January 2022 and December 2024. Quantitative data were extracted from hospital registries and REDCap, while qualitative data were obtained from key informant interviews with 17 healthcare workers. Quantitative data were analyzed using SPSS v29.0, while qualitative transcripts were thematically analyzed using NVivo software version 15 to explore operational factors influencing implementation. A total of 10,711 newborns were screened across the two hospitals. Seventy-four (0.70%) newborns had homozygous SCD (HbS/S), whereas 1325 (12.53%) had sickle cell trait (HbA/S). Enrolment of infants diagnosed with SCD into comprehensive care declined substantially over time, from 65.6% in 2022 to 10.5% in 2024 at Temeke RRH, while Amana RRH recorded no enrolments beyond the first year of implementation. Qualitative findings highlighted facilitators for NBS such as maternal awareness, interdepartmental collaboration, and the availability of trained staff. However, implementation was hindered by inadequate refresher training, delayed staff incentives, supply shortages, and parental hesitancy influenced by cultural beliefs. This evaluation found a substantial decline in enrolment of newborns diagnosed with SCD into comprehensive care, driven by key operational challenges. Although early implementation benefited from trained, committed staff and interdepartmental collaboration, sustainability was limited by inadequate refresher training, delayed incentives, supply shortages, and parental hesitancy. Addressing these gaps through regular capacity building, strengthened supply chains, timely incentives, and culturally sensitive community education is critical to improving enrolment, continuity of care, and informing national scale-up of NBS for SCD in Tanzania. Full article

Allogeneic hematopoietic cell transplantation (HCT) has been used for decades to treat certain malignant and non-malignant hematological conditions, but challenges remain. Increased understanding of disease mechanisms and recent developments in genome editing have enabled alternative strategies utilizing gene-edited autologous HCT and many of these have progressed to the clinic. We present here a comprehensive review of clinical trials of gene-edited autologous hematopoietic stem cells for the treatment of hemoglobinopathies and immunodeficiencies. Searches of major international clinical trial registries were carried out using specific key words. In total, 44 interventional clinical trials investigating gene-edited autologous stem cell therapies were identified, with CASGEVY (exagamglogene autotemcel) being the only product approved to date. Hemoglobinopathies were the most common indication (n = 37) followed by immunodeficiencies (n = 4), with single trials in HIV-1 infection, pyruvate kinase deficiency and limb–girdle muscular dystrophy. Gene-editing strategies fall into three categories: disruption of the BCL11A erythroid enhancer, editing of the γ-globin promoter and direct correction or disruption of disease-relevant genes. CD34⁺ hematopoietic stem and progenitor cells are the most common cell types edited, and CRISPR-Cas9 is the most widely used gene-editing modality. While results are encouraging, efficient intracellular delivery of gene-editing tools, editing efficiencies and off-target editing remain challenges for the field. Full article

Background: Sickle cell disease (SCD) is a hereditary disorder affecting red blood cells’ shape and functional capacity. Individuals with SCD report relatively high co-occurrence of neurodevelopmental disorders (NDDs). In addition, these children also have higher rates of enuresis (incontinence) and pica, disorders prevalent in children with developmental delays. Both enuresis and pica can have negative effects on mental health, but their pathophysiology, especially in SCD, remains unclear. Objectives: The objective of this study was to determine the rates of pica and enuresis in a pediatric SCD clinic to compare the co-occurrence of NDDs and enuresis/pica. Methods: To do so, we performed a cross-sectional explanatory retrospective chart review of 275 pediatric SCD patients. Results: Our SCD cohort had a 27% prevalence of enuresis, 9% prevalence of pica, and 24% prevalence of one or more NDDs. We noted significant inter-group overlap between pica/enuresis and other risk SCD severity factors. NDDs were approximately twice as frequent in SCD patients with pica or enuresis compared to those without. While pica was associated with HbSβ⁺, it was not linked to disease severity indicators. Enuresis was associated with hydroxyurea usage (66.7% vs. 42.6%, p = 0.001) and reticulocyte counts, indicative of higher disease severity. Conclusions: Clinically, these results are the first to show co-occurrence between pica, enuresis, and NDDs in SCD. We suggest that the occurrence of pica or enuresis may serve as an indicator for previously unknown NDD risk. Together, these results underscore the need for targeted screenings of pica and enuresis in SCD populations. Full article

In traditional medicine, laboratory tests are essential tools used to evaluate practices in healthcare that use natural products, particularly when there are few established treatments such as in the case of chronic diseases like sickle cell disease (SCD). SCD is a genetic hemoglobin disorder associated with hemolysis, oxidative stress, inflammation, and vaso-occlusive complications. This study aims to document medicinal plants used in the management of SCD and the traditional practices associated with their use, in order to assess their added value in relation to biological activities relevant to SCD. First, this study carried out an ethnobotanical survey at Kisangani, with 384 participants. A total of 201 respondents, 58% of whom were women, identified 45 medicinal plant species from 30 families. They reported the use of sugar, caramel, ash, and lemon juice as additives in traditional remedies. Based on several criteria, Alchornea cordifolia Müll. Arg. and Hibiscus tiliaceus L. were selected for laboratory evaluation. Their leaves were collected from arid and marshy soils and prepared according to the respondents’ descriptions for antioxidant and anti-inflammatory assessments. A. cordifolia showed significantly higher activities than H. tiliaceus regarding antioxidant (p = 0.001) and anti-inflammatory (p = 0.01) properties. Soil type was observed to influence the bioactivity of H. tiliaceus, with better performance in marshy soil samples. Sugar and caramel were found to reduce antioxidant activity, whereas ash and lemon juice preserved it without markedly altering anti-inflammatory effects. These findings are promising for supporting local knowledge about these two plant species. Full article

Background and Clinical Significance: Sickle cell vaso-occlusive crisis (VOC) may present with severe refractory pain that is difficult to control despite guideline-directed multimodal therapy and high-dose opioids. Case Presentation: We report an adult with VOC and severe, opioid-refractory anterior thigh and leg pain who was treated with bilateral, ultrasound-guided continuous femoral nerve catheters (0.5% bupivacaine bolus per side followed by infusion of 0.2% ropivacaine at 5 mL/h each). Twenty-four-hour opioid use decreased by 76% from 44 mg intravenous hydromorphone (880 MME) before block placement to 10.4 mg (208 MME) after catheter initiation. Pain scores declined significantly from 10/10 to 3/10, facilitating mobilization and expediting discharge of the patient. No local anesthetic systemic toxicity occurred, and transient quadriceps weakness was managed with fall-risk precautions. IRB approval for this case report was waived per our institution policy. Conclusions: In select adults with VOC and predominant anterior thigh/leg pain, bilateral continuous femoral nerve catheters may provide rapid analgesia and substantial opioid-sparing benefits as part of multidisciplinary care. These findings are hypothesis-generating and support prospective evaluation of continuous peripheral nerve block strategies in VOC. Full article

Background/Objectives: Non-typhoidal Salmonella (NTS) species are well-recognized causes of invasive infection in patients with sickle cell disease (SCD), with a particular predilection for the musculoskeletal system. Although Salmonella osteomyelitis is well described in this population, septic arthritis is uncommon, especially involving the shoulder joint. We describe a case of NTS bacteremia complicated by native shoulder septic arthritis in a patient with SCD and review its clinical implications. Methods: We report the clinical course, diagnostic evaluation, microbiologic findings, imaging studies, and management of a 22-year-old man with homozygous SCD who presented with a vaso-occlusive pain crisis and subsequently developed severe sepsis with persistent Salmonella enterica bacteremia following ingestion of undercooked poultry. Persistent bacteremia prompted further evaluation for metastatic infection using advanced imaging and diagnostic arthrocentesis. Results: Whole-body imaging identified septic arthritis of the native right shoulder, which was confirmed by synovial fluid cultures growing Salmonella species. The patient underwent arthroscopic irrigation and debridement for source control. Antimicrobial therapy was narrowed to intravenous ceftriaxone based on susceptibility data and continued for six weeks. The patient demonstrated clinical improvement with resolution of bacteremia and was discharged to rehabilitation to complete therapy. Conclusions: This case highlights the importance of a careful exposure history, including foodborne sources, in patients with SCD presenting with invasive Salmonella infection. Persistent bacteremia should prompt early investigation for metastatic foci, and timely surgical source control combined with targeted antimicrobial therapy is essential for optimal outcomes in this population. Full article

Background: Sickle cell disease (SCD) patients have increased susceptibility to infections, particularly encapsulated bacterial pathogens such as Streptococcus pneumoniae and Haemophilus influenzae type b. Hyposplenism as well as immune defects in SCD result in increased risks for infections; these are the most frequent complications in individuals with SCD. This study was performed within the African Research and Innovative initiative for Sickle cell Education (ARISE, EC GA No 824021) project to develop best practices in the clinical management of SCD. In this retrospective study we aimed to determine the most prevalent reported infections among SCD patients’ records during clinic visits at Ahmadu Bello University Teaching Hospital, Zaria, Nigeria. Methods: The medical records of 1961 paediatric SCD patients from 1998 to 2023 were extracted and reviewed from a pilot electronic registry using a structural query. The data analysed patterns of infections reported during clinic visits at the ABUTH, Zaria, Nigeria. Results: 458 subjects (23.4%) manifesting at least one infection, of whom 392 (19.9%) subjects had a single infection (bacterial or parasitic) and 173 (8.8%) had more than one infection (bacterial and parasitic). Conclusions: Bacterial and parasitic infections are a significant complication of SCD patients attending a tertiary institution in northern Nigeria. Full article

The All of Us Researcher Academy Internship Program provided a 3-month experiential learning opportunity for graduate and undergraduate students to train on analyzing health data from the All of Us Research Program. Thirteen interns were paired with mentors who have ongoing projects using the All of Us Researcher Workbench, a cloud-based data analysis platform. Interns also participated in networking activities, attended weekly internship supervisor and mentor meetings, and had access to virtual courses. The internship concluded with virtual presentations to share project results. Topics studied included sickle cell disease, cancer, diabetes, sleep disorders, allergic conditions, cardiovascular health, mental health, and healthcare access. The purpose of this evaluation study was to assess the All of Us Researcher Academy Internship Program’s impact on student outcomes during the first two cohorts (2023 and 2024). The study employed a post-only evaluation design. Ten interns completed post-internship surveys that inquired about their overall internship experience, Researcher Workbench use, and research skills development. The 2024 cohort also participated in a focus group discussion that probed their perceptions about the internship experience. Evaluation results revealed that 90% of interns strongly agreed that their overall research skills and self-efficacy improved, and 80% of interns reported interest in future use of the Researcher Workbench. Interns offered positive feedback on their mentorship experiences and reported a strong sense of support and belonging. The All of Us Researcher Academy Internship Program offers an effective model for skills-based experiential learning in biomedical research. Full article

Executive function (EF) impairments are common in children with intellectual and developmental disabilities and have a significant impact on learning and daily life. Cognitive training programs aimed at strengthening EFs may show limited feasibility and generalization. However, recent studies suggest that ecological, curriculum-embedded problem-solving activities may be more promising. This multiple-baseline single-case study tested the feasibility and efficacy of a short computational thinking and coding intervention based on problem-solving for children with sickle cell disease, a hemoglobinopathy associated with cognitive decline and EF deficits. The trial followed the What Works Clearinghouse (WWC) Version 5 guidelines for single-case research. Three 7–8-year-old children with lower-range IQ (71–82) and EF impairments completed 11 coding sessions over 5–6 weeks using code.org, with pre/post assessments of non-verbal EF (planning, inhibition, and switching), and verbal EF skills (verbal working memory, phonological fluency and semantic fluency). Results showed 100% adherence to the intervention, significant improvement in coding (IRD range = 0.69–0.79), with positive transfer effects on nonverbal planning skills (gains > 2 z-scores) and also verbal fluency (z-score gains ranging from 0.47 to 1.04). Inter-individual variability in effects was related to the child’s individual cognitive profile. Findings suggest that problem-solving, coding-based activities can be feasible and potentially beneficial for children with significant EF impairments. Full article

Hydroxyurea (HU) is a ribonucleotide reductase inhibitor widely used for the treatment of sickle cell disease and myeloproliferative disorders, yet a precise nitric oxide (NO) synthase (NOS)-dependent mechanism remains incompletely defined. The role of NOS3 in HU-mediated proliferation, cell cycle, and apoptosis was analyzed in HEL92.1.7 erythroleukemic cells and primary mouse erythroid progenitors upon genetic knockdown/knockout and pharmacological NOS2/NOS3 inhibition. NOS3 expression, phosphorylation, NO and citrulline production, and protein nitrosylation were assessed via immunoblotting and biochemical assays. Computational docking and molecular dynamics simulations were performed to examine the interaction between HU and NOS3. HU enhanced NOS3 expression and phosphorylation, leading to increased NO and citrulline production. Computational analysis predicted HU binding within the NOS3 active site, whereas functional activation was AKT1-dependent. A biotin switch assay revealed cooperative NOS2-/NOS3-mediated protein nitrosylation under HU treatment. NOS3 depletion or inhibition abrogated HU-induced S-phase accumulation and restored cell proliferation. NOS3 protein depletion increased late apoptosis in erythroleukemic cells, while in murine erythroid cells, both Nos3 deficiency and inhibition decreased early and increased late apoptosis. NOS2 and NOS3 act as complementary mediators of proliferation and apoptosis, with NOS3 playing a distinct role in HU-induced proliferation arrest in erythroid cells. These findings highlight the therapeutic potential of NOS targeting to enhance the efficacy of HU and overcome resistance in hematologic malignancies. Full article

Background/Objectives: Thalassemia and sickle cell anemia (SCA) patients require regular blood transfusions, a necessity that increases the risk of alloimmunization and complicates subsequent transfusion management. Methods: This retrospective cohort study, conducted at King Saud Medical City (KSMC) and King Fahad Medical City (KFMC) between 2018 and 2022, evaluated the frequency and risk factors of alloimmunization among 144 transfusion-dependent patients in Riyadh, Saudi Arabia. Results: By reviewing clinical and transfusion records alongside antibody screening results, the study found an overall alloimmunization prevalence of 20.1%. Notably, females exhibited a significantly higher rate (13.2%) compared to males (6.8%; p = 0.003), and younger patients (<20 years) showed a higher prevalence than older cohorts (p = 0.004). Analysis of ABO blood groups revealed that group A patients had a significantly lower alloimmunization rate (7.5%) compared to non-A patients (23.1%; p = 0.018), a finding that raises hypotheses about differential immune responsiveness but requires confirmation in larger studies. Group B showed the highest rate (35.3%), though this did not reach statistical significance after correction for multiple comparisons. RhD status was not significantly associated with alloimmunization. The most frequent alloantibodies identified were anti-E (31.3%), anti-K (12.5%), anti-D (10.4%), and anti-C (10.4%). Logistic regression further identified gender as a significant predictor (OR = 0.270; 95% CI: 0.113–0.646). Conclusions: Given that alloimmunization rates in Riyadh are moderately high—particularly among females and specific blood groups—and that the antibody profile (anti-E, anti-K, anti-C, anti-D) mirrors patterns seen in populations with recipient–donor ethnic mismatches, implementing extended blood group phenotyping for at least Rh (C, c, E, e) and Kell antigens prior to the first transfusion, and incorporating these findings into donor selection protocols, is critical to mitigating these risks. Full article

Background/Objective: The most common hemoglobin disorder in the world is SCD. The majority of SCD cases come from Africa, accounting for up to two-thirds of the 300,000 annual births of individuals with SCD worldwide. In Tanzania, 11,000–14,000 babies are born with SCD each year. Despite treatment advancement, pain is still an attributable cause of admissions among patients with SCD. However, data are still lacking regarding the adequacy of pain control in patients with SCD in Tanzania. The aim of this study was to determine factors affecting pain control among patients with SCD presenting with painful events at Mwananyamala Regional Referral Hospital (MRRH) and Muhimbili National Hospital (MNH) in Dar es Salaam, Tanzania. Methods: This was a cross-sectional study conducted at MRRH and MNH, which are tertiary referral hospitals in Dar es Salaam, Tanzania. Patients with SCD aged 8 years and above who presented at the hospitals with painful events (from August 2022 to February 2023) were enrolled in the study. We used a structured questionnaire to collect data on participants’ socio-demographic characteristics and clinical parameters. The adequacy of pain control was assessed using the WHO Pain Management Index. Multivariable binary logistic regression was used to determine factors associated with pain control. Differences were considered statistically significant when the p-value was <0.05. Results: A total of 390 patients with SCD were analyzed. The mean age (±SD) was 15 (±6) years. Most patients were recruited from outpatient clinics (88.2%). The male-to-female ratio was 1:1. The majority of patients had less than three pain episodes per year (77.9%), and about 64.6% presented to the hospital with mild pain. The proportion of patients on hydroxyurea was 62.3%. Furthermore, one-third of patients had inadequate pain control. Factors associated with inadequate pain control included receiving initial pain management in other health facilities (adjusted odds ratio [aOR] and 95% confidence interval [CI] = 2.5 (1.5–4.5), p = 0.001), presenting to the hospital with moderate pain (aOR = 2.2, 95% CI [1.3–3.8], p = 0.0060), and presenting to the hospital with a fever (aOR = 3.8, 95% CI [1.1–13.9], p = 0.04). Having severe pain and receiving initial treatment at MRRH and MNH seemed to be protective factors (aOR = 0.33, 95% CI [0.11–0.97], p = 0.04, and aOR = 0.29, 95% CI [0.14–0.61], p = 0.001, respectively). Conclusions: A considerable proportion of patients with SCD receive suboptimal pain control. Receiving initial pain management from another healthcare facility, presenting to the hospital with moderate pain, and having a fever were associated with inadequate pain control. Further research is warranted to elucidate ways of optimizing the management of pain in patients with SCD in Tanzania. Full article

Background and Objective: Sickle cell disease (SCD) is an inherited blood disorder associated with recurrent painful crises. Sickle cell pain crises are a significant source of distress for patients and contribute substantially to hospital utilization among SCD populations. Many children with SCD also experience chronic pain, which is often multifactorial in nature. The management of both acute and chronic pain in SCD commonly relies on opioid medications. Acute and chronic use of opioids is associated with health risks and potential complications, which has raised interest in alternatives. Buprenorphine is a partial μ-receptor agonist with strong affinity that confers pain relief and may have an improved side-effect profile. While there is emerging evidence for its use in adult patients, the data is less developed in pediatrics. Methods: A scoping review was designed in accordance with PRISMA guidelines to systematically explore the literature on buprenorphine use in pain management for children with sickle cell disease (SCD). Results: This review shows that the published literature in this area is of low quality and extremely limited, and there is a lack of trials specifically designed to address the use of buprenorphine for this patient population. Studies are limited in their generalizability but suggest that buprenorphine may be useful in managing pain in this population. Conclusions: While promising, more data is required both retrospectively and prospectively to understand the utility of buprenorphine. The development of pediatric-specific protocols for transitioning from full µ-receptor agonist opioids to buprenorphine is also needed. Full article