Reversibility of Cognitive Deficits and Functional Connectivity With Transfusion in Children With Sickle Cell Disease.

BACKGROUND AND OBJECTIVES: People with sickle cell disease (SCD) are at risk of cognitive dysfunction independent of stroke. Diminished functional connectivity in select large-scale networks and white matter integrity reflect the neurologic consequences of SCD. Because chronic transfusion therapy is neuroprotective in preventing stroke and strengthening executive function abilities in people with SCD, we hypothesized that red blood cell (RBC) transfusion facilitates the acute reversal of disruptions in functional connectivity while white matter integrity remains unaffected. METHODS: Children with SCD receiving chronic transfusion therapy underwent a brain MRI measuring white matter integrity with diffusion tensor imaging and resting-state functional connectivity within 3 days before and after transfusion of RBCs. Cognitive assessments with the NIH Toolbox were acquired after transfusion and then immediately before the following transfusion cycle. RESULTS: Sixteen children with a median age of 12.5 years were included. Global assessments of functional connectivity using homotopy (p = 0.234) or modularity (p = 0.796) did not differ with transfusion. Functional connectivity within the frontoparietal network significantly strengthened after transfusion (median intranetwork Z-score 0.21 [0.17-0.30] before transfusion, 0.29 [0.20-0.36] after transfusion, p < 0.001), while there was not a significant change seen within the sensory motor, visual, auditory, default mode, dorsal attention, or cingulo-opercular networks. Corresponding to the change within the frontoparietal network, there was a significant improvement in executive function abilities after transfusion (median executive function composite score 87.7 [81.3-90.7] before transfusion, 90.3 [84.3-93.7] after transfusion, p = 0.021). Participants with stronger connectivity in the frontoparietal network before transfusion had a significantly greater improvement in the executive function composite score with transfusion (r = 0.565, 95% CI 0.020-0.851, p = 0.044). While functional connectivity and executive abilities strengthened with transfusion, there was not a significant change in white matter integrity as assessed by fractional anisotropy and mean diffusivity within 16 white matter tracts or globally with tract-based spatial statistics. DISCUSSION: Strengthening of functional connectivity with concomitant improvement in executive function abilities with transfusion suggests that functional connectivity MRI could be used as a biomarker for acutely reversible neurocognitive injury as novel therapeutics are developed for people with SCD.

Cost analysis for initiating an integrated package of essential non-communicable disease interventions (PEN-Plus) in Kondoa District Hospital, Tanzania: a time-driven activity-based costing (TDABC) study protocol.

INTRODUCTION: Non-communicable diseases (NCDs) constitute approximately 74% of global mortality, with 77% of these deaths occurring in low-income and middle-income countries. Tanzania exemplifies this situation, as the percentage of total disability-adjusted life years attributed to NCDs has doubled over the past 30 years, from 18% to 36%. To mitigate the escalating burden of severe NCDs, the Tanzanian government, in collaboration with local and international partners, seeks to extend the integrated package of essential interventions for severe NCDs (PEN-Plus) to district-level facilities, thereby improving accessibility. This study aims to estimate the cost of initiating PEN-Plus for rheumatic heart disease, sickle cell disease and type 1 diabetes at Kondoa district hospital in Tanzania. METHODS AND ANALYSIS: We will employ time-driven activity-based costing (TDABC) to quantify the capacity cost rates (CCR), and capital and recurrent costs associated with the implementation of PEN-Plus. Data on resource consumption will be collected through direct observations and interviews with nurses, the medical officer in charge and the heads of laboratory and pharmacy units/departments. Data on contact times for targeted NCDs will be collected by observing a sample of patients as they move through the care delivery pathway. Data cleaning and analysis will be done using Microsoft Excel. ETHICS AND DISSEMINATION: Ethical approval to conduct the study has been waived by the Norwegian Regional Ethics Committee and was granted by the Tanzanian National Health Research Ethics Committee NIMR/HQ/R.8a/Vol.IX/4475. A written informed consent will be provided to the study participants. This protocol has been disseminated in the Bergen Centre for Ethics and Priority Setting International Symposium, Norway and the 11th Muhimbili University of Health and Allied Sciences Scientific Conference, Tanzania in 2023. The findings will be published in peer-reviewed journals for use by the academic community, researchers and health practitioners.

Patterns of primary and specialty care among children with sickle cell anemia.

BACKGROUND AND OBJECTIVE: National guidelines recommend that children with sickle cell anemia (SCA) be seen regularly by primary care providers (PCPs) as well as hematologists to receive comprehensive, multidisciplinary care. The objective is to characterize the patterns of primary and hematology care for children with SCA in Michigan. METHODS: Using validated claims definitions, children ages 1-17 years with SCA were identified using Michigan Medicaid administrative claims from 2010 to 2018. We calculated the number of outpatient PCP and hematologist visits per person-year, as well as the proportion of children with at least one visit to a PCP, hematologist, or both a PCP and hematologist annually. Negative binomial regression was used to calculate annual rates of visits for each provider type. RESULTS: A total of 875 children contributed 2889 person-years. Of the total 22,570 outpatient visits, 52% were with a PCP and 34% with a hematologist. Annually, 87%-93% of children had a visit with a PCP, and 63%-85% had a visit with a hematologist. Approximately 66% of total person-years had both visit types within a year. The annual rate ranged from 2.3 to 2.5 for hematologist visits and from 3.7 to 4.1 for PCP visits. CONCLUSIONS: Substantial gaps exist in the receipt of annual hematology care. Given that the majority of children with SCA see a PCP annually, strategies to leverage primary care visits experienced by this population may be needed to increase receipt of SCA-specific services.

New Horizons in Emergency Department Management of Pediatric Sickle Cell Disease.

ABSTRACT: Sickle cell disease (SCD) is an important topic for emergency medicine audiences because complications of the disease account for a large proportion of hematologic emergencies that are seen in the emergency department each year. Early recognition and aggressive management of emergency complications of SCD can help to reduce the morbidity and mortality associated with this disease. Although the treatment recommendations for some complications of SCD are based on expert opinion, there has been advancement in the understanding of the pathogenesis of the disease and evidence regarding the treatment options available for managing acute complications. This continuing medical education article will provide a summary of the clinical manifestation and management of the most common acute complications of SCD: infection, vaso-occlusive episode, acute chest syndrome, splenic sequestration, stroke, and priapism.

Malnutrition in sickle cell anemia: Prevalence, impact, and interventions: A Review.

Sickle Cell Anemia (SCA) is a hereditary hemoglobinopathy characterized by chronic hemolytic anemia, vaso-occlusive events, and a wide range of clinical complications. Malnutrition, often an underexplored aspect of this complex condition, plays a critical role in disease management and overall patient well-being. This publication provides a comprehensive review of the prevalence, impact, and interventions related to malnutrition in individuals with SCA. A thorough literature review reveals the multifaceted challenges faced by SCA patients in maintaining adequate nutrition. The pathophysiology of SCA, involving chronic inflammation, oxidative stress, and hypermetabolism, contributes to increased nutritional requirements and altered dietary patterns. Factors such as reduced appetite, nutrient malabsorption, dietary restrictions, and socioeconomic disparities further exacerbate the risk of malnutrition. Malnutrition is a prevalent issue among individuals with SCA, affecting patients of different age groups and disease severities. Nutritional deficiencies, including vitamins, minerals, and essential nutrients, are common in this population. The impact of malnutrition on disease outcomes is significant, with associations between nutrient status and complications such as pain crises, infections, and impaired quality of life. This paper also reviews nutritional interventions aimed at addressing malnutrition in SCA patients. While dietary counseling, supplementation, and personalized nutrition plans have shown promise in improving nutritional status, challenges such as patient adherence and access to healthcare must be addressed to optimize their effectiveness.

Current and Future Therapeutics for Treating Patients with Sickle Cell Disease.

Sickle cell disease (SCD) is the most common genetic blood disorder in the United States, with over 100,000 people suffering from this debilitating disease. SCD is caused by abnormal hemoglobin (Hb) variants that interfere with normal red blood cell (RBC) function. Research on SCD has led to the development and approval of several new SCD therapies in recent years. The recent FDA-approved novel gene therapies are potentially curative, giving patients an additional option besides a hematopoietic bone marrow transplant. Despite the promise of existing therapies, questions remain regarding their long-term pharmacological effects on adults and children. These questions, along with the exorbitant cost of the new gene therapies, justify additional research into more effective therapeutic options. Continual research in this field focuses on not only developing cheaper, more effective cures/treatments but also investigating the physiological effects of the current therapies on SCD patients, particularly on the brain and kidneys. In this article, we undertake a comprehensive review of ongoing clinical trials with completion dates in 2024 or later. Our exploration provides insights into the landscape of current therapeutics and emerging novel therapies designed to combat and potentially eradicate SCD, including the latest FDA-approved gene therapies.

Managing gastrointestinal challenges: Diarrhea in sickle cell anemia.

Sickle cell anemia (SCA), a hereditary hemoglobinopathy, is characterized by the presence of abnormal hemoglobin and has long been associated with a wide range of complications. While much attention has been given to the condition hematological aspects, gastrointestinal complications, particularly diarrhea, have been relatively understudied and often overlooked. This publication delves into the management of gastrointestinal challenges, with a focus on diarrhea, in individuals living with SCA. The pathophysiology of SCA is intrinsically linked to gastrointestinal complications, and diarrhea is a common manifestation of this condition. This abstract publication outlines the key elements discussed in the full-length work, which includes the clinical presentation of diarrhea in these patients, the diagnostic tools used to evaluate the condition, and various management strategies to alleviate symptoms and enhance the overall quality of life for affected individuals. The paper emphasizes the importance of patient education, offering healthcare professionals valuable insights into how to inform and support patients in managing their conditions effectively. It also highlights the need for continued research to further our understanding of gastrointestinal challenges in SCA and to identify potential areas for future therapeutic interventions. Ultimately, the comprehensive management of diarrhea in individuals with SCA is vital for their overall well-being. This publication serves as a valuable resource for healthcare providers, researchers, and caregivers in addressing the gastrointestinal challenges that accompany SCA, ultimately working toward a better quality of life for those affected by this condition.

Prevention of potential delayed hemolytic transfusion reaction in two sickle cell patients using intravenous immunoglobulins and steroids before and after red blood cell exchange with antigen positive units and review literature.

Emergent Red Blood Cell (RBC) exchange is indicated in sickle cell disease (SCD) patients with severe acute chest syndrome. However, fully matched RBC units may not be available for patients with multiple RBC antibodies. Intravenous immunoglobulin (IVIG) and steroids were reported for preventing potential delayed hemolytic transfusion reaction (HTR) in simple transfusion of antigen-positive RBCs. We investigated the efficacy and safety of IVIG and steroids in two SCD patients presented with acute chest syndrome receiving RBC exchange with multiple incompatible units. The first patient had multiple historical alloantibodies, including anti-Jsb, although none of them were reactive. IVIG (1 g/kg) was given before and after RBC exchange with methylprednisolone (500 mg IV) one hour before exchange. Her sickle hemoglobin (HbS) was reduced from 89.4% to 17.4% after the exchange with five Jsb-positive units. The patient improved clinically without acute or delayed hemolysis. The second patient had reactive anti-Jsb on two different admissions 18 months apart. Only one of the sixteen units used in the exchanges was Jsb negative. He received the same IVIG regimen during both admissions but 100 mg IV hydrocortisone instead of methylprednisolone. His HbS was reduced from 63.4% to 22.4% after the first exchange. Significant clinical improvements were achieved after both exchanges. No delayed HTR was observed. Our experience of these two patients suggested that IVIG and steroids may be used in preventing potential delayed HTR in some SCD patients with rare antibodies receiving large amounts of antigen-positive RBC products.

Utility of hemoglobin electrophoresis to distinguish between severe delayed hemolytic transfusion reaction versus hyperhemolysis syndrome.

Delayed hemolytic transfusion reaction (DHTR) and hyperhemolysis syndrome (HHS) are both complications of red blood cell transfusions in patients with sickle cell disease.Clinically, both present with hemolysis and can be difficult to differentiate. Hemoglobin electrophoresis may aid in the diagnosis. Herein we describe a case in which a patient with hemoglobin SC disease presented with features of severe hemolysis several days after initiation of red blood cell exchange. Increase in reticulocyte count and complete absence of hemoglobin A on electrophoresis during this event supported the diagnosis of severe DHTR, indicating a rapid and selective destruction of the transfused red blood cells. Ability to interpret the hemoglobin electrophoresis can help clinicians distinguish between these two severe transfusion complications in patients living with sickle cell disease. It is important to identify the presence or absence of concomitant HHS, as patients with HHS tend to have a worse prognosis and there is a higher rate of recurrence of HHS with subsequent transfusions. Accurate diagnosis can lead to prompt management and decrease morbidity and mortality.

[Population characterization of mutations for sickle cell anemia and its treatment: One step towards personalized medicine for the disease]. / Caracterización poblacional de mutaciones relevantes para la Anemia Falciforme y su tratamiento: Un paso hacia la personalización de la enfermedad.

Sickle cell anemia (SCA) is the most common genetic disease worldwide. There are countries with massive public health programs for early detection of this condition. In the literature, several specific haplotypes or single-base polymorphic variants (SNPs) have been associated with the SCA prognosis. OBJECTIVE: To demonstrate the significant correlation of SNPs relevant to the diagnosis and prognosis of SCA among different ethnic groups. METHODOLOGY: we analyzed population frequencies and correlations of several SNPs related to the prognosis of SCA (i.e., baseline fetal hemoglobin levels), response to hydroxyurea treatment, and response to other drugs used in the SCA treatment, collected from validated genomic databases among different ethnic groups. RESULTS: The calculation of the Hardy-Weinberg equilibrium and the logistic regression was successful in classifying the ethnic groups as African (0 = 0.78, 1 = 0.89), and with a lower efficiency as American (AMR) (0 = 0.88, 1 = 0.00), East Asian (EAS) (0 = 0.80, 1 = 0.00), European (EUR) (0 = 0.79, 1 = 0.00), and South Asian (SAS) (0 = 0.80, 1 = 0.00). CONCLUSIONS: The results extend those from previous reports and show that the profile of most of the SNPs studied presented statistically significant distributions among general ethnic groups, pointing to the need to carry out massive early screening of relevant SNPs for SCA in patients diagnosed with this disease. It is concluded that the application of a broad mutation detection program will lead to a more personalized and efficient response in the treatment of SCA.

Translational Research and Health Equity: Gene Therapies for Sickle Cell Disease as a Case Study.

In August of 2023, the National Academies of Science, Engineering, and Medicine published a timely report titled "Toward Equitable Innovation in Health and Medicine: A Framework." Here, we review some of the key contributions of the report, focusing on two dimensions of equity: input equity and deployment equity. We then use the example of new gene therapies to treat sickle cell disease (SCD) as a case study of input and deployment equity in translational research. The SCD case study illustrates the need for a kind of translational bioethics with deep understanding of lived experiences and clinical realities as well as a high degree of economic and policy sophistication.

Effect of nutritional supplementation on bone mineral density in children with sickle cell disease: protocol for an open-label, randomised controlled clinical trial.

INTRODUCTION: Children with sickle cell disease show a significant decrease in bone mineral density, an increase in resting energy expenditure of more than 15%, a decrease in fat and lean mass as well as a significant increase in protein turnover, particularly in bone tissue. This study aims to evaluate the effectiveness of an increase in food intake on bone mineral density and the clinical and biological complications of paediatric sickle cell disease. METHODS AND ANALYSIS: The study is designed as an open-label randomised controlled clinical trial conducted in the Paediatrics Unit of the Orléans University Hospital Centre. Participants aged 3-16 years will be randomly divided into two groups: the intervention group will receive oral nutritional supplements (pharmacological nutritional hypercaloric products) while the control group will receive age-appropriate and gender-appropriate nutritional intake during 12 months. Total body less head bone mineral density will be measured at the beginning and the end of the trial. A rigorous nutritional follow-up by weekly 24 hours recall dietary assessment and planned contacts every 6 weeks will be carried out throughout the study. A school absenteeism questionnaire, intended to reflect the patient's school productivity, will be completed by participants and parents every 3 months. Blood samples of each patient of both groups will be stocked at the beginning and at the end of the trial, for future biological trial. Clinical and biological complications will be regularly monitored. ETHICS AND DISSEMINATION: The protocol has been approved by the French ethics committee (Comité de Protection des Personnes Sud-Ouest et Outre-Mer 2, Toulouse; approval no: 2-20-092 id9534). Children and their parents will give informed consent to participate in the study before taking part. Results will be disseminated through peer-reviewed journals or international academic conferences. TRIAL REGISTRATION NUMBER: NCT04754711.

Acute care utilization among individuals with sickle cell disease and related cardiopulmonary and renal complications.

Cardiopulmonary and renal end organ (CPR) complications are associated with early mortality among individuals with sickle cell disease (SCD). However, there is limited knowledge regarding acute care utilization for individuals with SCD and CPR complications. Our objective was to determine the prevalence of CPR complications in a state specific SCD population and compare acute care utilization among individuals with and without CPR complications. We leveraged 2017-2020 data for individuals with SCD identified by the Sickle Cell Data Collection program in Wisconsin. The prevalence of CPR complications is determined for distinct age groups. Generalized linear models adjusted for age compared the rate of acute care visits/person/year among individuals who had cardiopulmonary only, renal only, both cardiopulmonary and renal, or no CPR complications. There were 1378 individuals with SCD, 52% females, mean (SD) age 28.3 (18.5) years; 48% had at least one CPR complication during the study period. The prevalence of CPR complications was higher in adults (69%) compared to pediatric (15%) and transition (51%) groups. Individuals with SCD and cardiopulmonary complications had higher acute visit rates than those without CPR complications (5.4 (IQR 5.0-5.8) vs 2.4 (IQR 2.1-2.5), p <0.001)). Acute care visit rates were similar between individuals with SCD who had renal only complications and no CPR complications (2.7 (IQR 2.5-3.0) vs 2.4 (2.1-2.5), p = 0.24). The high acute care visit rates, especially for those with cardiopulmonary complications, warrant further investigation to understand risk factors for CPR complications, the underlying reasons and identify effective disease management strategies.

[Transition in sickle cell disease - recommendations of the transition initiative sickle cell disease]. / Transition bei der Sichelzellkrankheit ­ Empfehlungen der Transitionsinitiative Sichelzellkrankheit.

Sickle cell disease is a rare, but complex multi-systemic disorder with high need of interdisciplinary and specialized care and new structural requirements. Besides care of those chronically sick patients, transition process is a vulnerable phase which highly influences further treatment. To make matters worse, patients often have migration background with subsequent communication problems. A national guidance for a standardized transition process is lacking in Germany. In context of a structured consensus process, the "transition initiative sickle cell disease" developed specific recommendations for a structured transition of sickle cell patients on the basis of the S3 transition guideline of the DGfTM. These recommendations should improve this vulnerable process in this complex disease to ensure adequate further treatment and to avoid acute and chronic complications but also mental, social or job-related issues. Besides improvement of quality of life, medical treatment and survival, health economic aspects arise. Documents were developed to support and facilitate the transition process and are available under www.sichelzellkrankheit.info/transition/.

Validating evidence for the knowledge, management and involvement of dentists in a dental approach to sickle-cell disease.

This study validated the content of an instrument designed to assess the knowledge, involvement (attitudes) and management (practice) of dentists relative to sickle-cell disease (KAPD-SCD). The instrument consisted of five domains composed of a total of thirteen items: I. Dentist's self-assessment relative to sickle-cell disease; II. Dentist's knowledge of the repercussions of sickle-cell disease on the stomatognathic system; III. Dentist's knowledge of the complications of sickle-cell disease in the stomatognathic system; IV. Dentist's knowledge concerning the dental management of sickle-cell disease patients; and V. Dentist's involvement in an approach to sickle-cell disease. Twelve experts assigned scores to each item of the instrument. The criteria were clarity, understanding and appropriateness, leaving open fields for comments. Descriptive and content analyses of the data were made. Each expert analyzed 39 assessment units. The percentages considered for agreement were high (>80%), medium (70%-80%), or low (<70%), and each item was maintained or revised according to the percentage observed. There was high consensus in 74% of the assessment units (the corresponding items were maintained), medium consensus in 24% of them (the corresponding items were revised), and disagreement in 2% of them, namely as regards the "appropriateness" of item 5 ("Are there oral complications in sickle-cell disease?"), which was revised. The final version of the instrument had 16 items for different applications such as in the clinical care program, teaching program, or research program, with different cut-off scores for each application. In conclusion, the level of agreement among experts showed evidence of the content validity of the instrument.

Management of diabetes mellitus patients with sickle cell anemia: Challenges and therapeutic approaches.

The coexistence of diabetes mellitus (DM) and sickle cell anemia (SCA) poses significant challenges in clinical management due to the complex interactions and overlapping complications associated with both conditions. Managing diabetes in individuals with SCA requires a comprehensive approach that addresses the unique physiological and pathological aspects of both diseases. This paper reviews the challenges encountered in the management of DM in patients with SCA and explores therapeutic strategies and approaches to optimize patient care. Challenges in the management of DM in individuals with SCA stem from several factors, including the impact of hemoglobin variants on glycemic control assessment, increased susceptibility to infections, altered immune response, and complications associated with both diseases. Moreover, the coexistence of SCA and DM heightens the susceptibility to infections due to compromised immune function, emphasizing the need for vigilant preventive measures, including vaccinations and close monitoring for infectious complications. Close collaboration among healthcare providers specializing in diabetes, hematology, and other relevant fields is crucial for developing comprehensive care plans. Individualized treatment strategies that balance glycemic control, pain management, and preventive care are essential to mitigate complications and optimize the overall health outcomes of patients with both DM and SCA. In conclusion, managing diabetes in the context of SCA necessitates a nuanced and patient-centered approach. By addressing the challenges and employing tailored therapeutic strategies, healthcare providers can improve the quality of life and health outcomes for individuals affected by both conditions.