Browsing by Subject "Sickle cell disease"
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Item Open Access Adherence and Quality of Life in Pediatric Sickle Cell Disease: A Pilot Mobile Health Intervention(2017) Anderson, Lindsay MarieChildren and adolescents with sickle cell disease (SCD) are at high risk for medical complications, neuropsychological sequelae, and lower overall quality of life. One target of intervention that can positively impact these outcomes is treatment adherence. Despite the known benefits of treatment adherence for health outcomes, children with SCD encounter several barriers that result in low overall levels of adherence and reduction of treatment benefits. Furthermore, little is known regarding the relationship between adherence and quality of life for this pediatric population. As such, two studies were conducted in order to (a) examine the relationship between treatment adherence and quality of life among youth with SCD, and (b) examine the feasibility, acceptability, and preliminary efficacy of a novel mobile health intervention to improve adherence among youth with SCD. For the first study, 46 children and adolescents with SCD and a caregiver were recruited. Results indicated that participants with good adherence had significantly higher parent-reported quality of life than participants with poor adherence. In contrast, based on child self-report, participants did not differ across quality of life domains. Subsequently, 43 participants were recruited to participate in the pilot intervention study, the Intensive Training Program (ITP). The intervention was conducted in two phases: Phase I recruited participants receiving iron chelation therapy to reduce the risk of iron overload associated with chronic red blood transfusions (n=11); Phase II broadened the scope of participants to those prescribed hydroxyurea (HU; n=32), a once daily oral medication. Results indicated that patients and their caregivers endorsed high levels of acceptance, ease of use, and satisfaction with mobile health technology. In addition, participants encountered several technological issues that limited access and resulted in poor compliance with the ITP for some participants early on in the study. Despite this, participants demonstrated significant increases in medication possession ratio (MPR) based on pharmacy refill as well as sustained improvements in disease knowledge. Adherent participants demonstrated significant decreases in outcomes related to caregiver burden as well as significantly lower pain impact when compared to non-adherent youth. In addition, children who were adherent reported quality of life and overall SCD-related functioning at a clinically-significant higher level when compared to those who were non-adherent. Implications for future research and application to clinical care are discussed.
Item Open Access Disease Knowledge and Readiness for Transition in Adolescents with Sickle Cell Disease in Jamaica: A Mixed-Methods Study(2018) Aly, MarwaIntroduction: Sickle cell disease (SCD) is a genetically inherited recessive blood disorder that affects millions of people worldwide. The management of SCD should and can be considered a collaborative team effort, and requires the comprehensive and coordinated support of several medical professionals. The rising number of adults living with SCD creates a need for long term therapeutic and management strategies as well as a better understanding of the transition from pediatric to adult care. The research goal for this project is to compare the two systems that exist for treatment of adolescents with SCD in Jamaica and the United States by assessing differences and similarities in patients’ readiness for adult treatment and their understanding of SCD and its management. Methods: This study was conducted in the Sickle Cell Unit at the University of West Indies (UWI) hospital in Kingston, Jamaica. Eligibility for this study was defined as patients with SCD, between the ages of 13-19, seeking treatment at the health facility in the University of the West Indies, who have no acute illness at the time of study. After a verbal and written consent process during check-in, each participant completed a demographic survey, disease knowledge questionnaire, the ASH Transition Readiness Assessment Questionnaire, and had the opportunity to participate in in-depth interviews. Following data collection, results subsequently with similar previously completed surveys from patients at the Duke University Sickle Cell Center. Results: Gender and socioeconomic factors were not associated with differences in assessment scores in Jamaica. Total scores for disease knowledge questionnaires increased with age, however mean scores for the 17-19 age group were 62.17% lower than Duke University patients of the same age. Self-evaluation with the ASH Transition Readiness Assessment also showed an increase in scores with age, and significant increases in disease knowledge and appointments sections in both the 13-14 and 17-19 age groups, estimated by a p-value of 0.023 and 0.006, respectively. The results, however, were also generally lower than similar Transition Readiness Assessment measures at Duke. In-depth interviews revealed patient insight into disease knowledge, treatment involvement and experiences with doctors, family, and in the clinic. Answers align with both questionnaires used in this study.
Item Open Access Hydroxyurea use and Plasmodium falciparum prevalence among children with sickle cell anemia in Homa Bay, Kenya; a cross sectional study(2019) Nantume, Assumpta SolomeHydroxyurea, a mainstay of sickle cell management in the developed world, offers a range of potential benefits to children with sickle cell disease. There is strong evidence that hydroxyurea induces production of fetal hemoglobin (HbF) in red blood cells, which is generally associated with reduced morbidity and fewer incidents of clinical events in sickle cell patients. Based on literature from in vitro investigations, it has also been suggested that hydroxyurea may confer some protection against malaria parasitemia by inhibiting proliferation of the malaria-causing parasite - Plasmodium falciparum.
The purpose of this study was to examine the effects hydroxyurea use on P. falciparum infection, parasite density, HbF and morbidity among children with sickle cell disease living in a malaria endemic setting. We analyzed baseline data of 95 children (aged 1 – 10 years) enrolled in the EPiTOMISE clinical trial (Enhancing Preventive Therapy of Malaria in children with Sickle cell anemia in East Africa) between January 2018 and September 2018.
Our analyses showed no significant difference in the prevalence of P. falciparum infection between hydroxyurea users and non-hydroxyurea users, prevalence ratio [95% CI] = 1.14 [0.76, 1.71]. Among infected children, median (IQR) log parasites densities were also similar between hydroxyurea users, -0.96 (-1.67, 0.41) and hydroxyurea non-users, -0.12 (-1.32, 3.48), p-value=0.146.
We did observe substantial hematological benefits among hydroxyurea users including an approximate 1 unit increase in median hemoglobin concentration and a 2.7-fold increase in median percentage HbF. However, this observation did not translate to any meaningful difference in the prevalence of morbidity events.
In agreement with the few studies on hydroxyurea use in malaria endemic settings, these results suggest that there may be no added risk of P. falciparum infection to sickle cell patients who routinely use hydroxyurea. Furthermore, our results reflect that hydroxyurea use is associated with increased HbF and a better hematological profile in this population. There is need for more research on hydroxyurea use in sub-Saharan Africa to help resolve any existing concerns and conflicting data in the current body of literature.
Item Open Access MEK1/2 as a Therapeutic Target in Sickle Cell Disease.(International journal of blood research and disorders, 2019-01) Zennadi, RahimaIdentification of novel therapeutic targets has improved diagnostics and treatment of many diseases. Many innovative treatment strategies have been developed based on the newly identified biomarkers and key molecules. Most of the research focused on ways to manipulate signaling pathways by activating or suppressing them, validate new therapeutic targets for treatment, and epigenetic treatment of diseases. With the identification of aberrations in multiple growth pathways, the focus then shifted to the small molecules involved in these pathways for targeted therapy. In this communication/short review, we highlight the importance of identification of abnormal activation of the mitogen-activated protein kinase (MAPK), ERK1/2, and its upstream mediator MEK1/2, in erythrocytes in patients with sickle cell disease (SCD) critical for the adhesive interactions of these cells with the endothelium, and leukocytes promoting circulatory obstruction leading to tissue ischemia and infraction. We also discuss how targeting this signaling cascade with MEK1/2 inhibitors can reverse acute vasoocclusive crises in SCD.Item Open Access Non-Pharmacological Approaches for Pain Management in Sickle Cell Disease: Development of a Mindfulness-Based Intervention(2016) Williams, HantsBackground: Sickle Cell Disease (SCD) is a genetic hematological disorder that affects more than 7 million people globally (NHLBI, 2009). It is estimated that 50% of adults with SCD experience pain on most days, with 1/3 experiencing chronic pain daily (Smith et al., 2008). Persons with SCD also experience higher levels of pain catastrophizing (feelings of helplessness, pain rumination and magnification) than other chronic pain conditions, which is associated with increases in pain intensity, pain behavior, analgesic consumption, frequency and duration of hospital visits, and with reduced daily activities (Sullivan, Bishop, & Pivik, 1995; Keefe et al., 2000; Gil et al., 1992 & 1993). Therefore effective interventions are needed that can successfully be used manage pain and pain-related outcomes (e.g., pain catastrophizing) in persons with SCD. A review of the literature demonstrated limited information regarding the feasibility and efficacy of non-pharmacological approaches for pain in persons with SCD, finding an average effect size of .33 on pain reduction across measurable non-pharmacological studies. Second, a prospective study on persons with SCD that received care for a vaso-occlusive crisis (VOC; N = 95) found: (1) high levels of patient reported depression (29%) and anxiety (34%), and (2) that unemployment was significantly associated with increased frequency of acute care encounters and hospital admissions per person. Research suggests that one promising category of non-pharmacological interventions for managing both physical and affective components of pain are Mindfulness-based Interventions (MBIs; Thompson et al., 2010; Cox et al., 2013). The primary goal of this dissertation was thus to develop and test the feasibility, acceptability, and efficacy of a telephonic MBI for pain catastrophizing in persons with SCD and chronic pain.
Methods: First, a telephonic MBI was developed through an informal process that involved iterative feedback from patients, clinical experts in SCD and pain management, social workers, psychologists, and mindfulness clinicians. Through this process, relevant topics and skills were selected to adapt in each MBI session. Second, a pilot randomized controlled trial was conducted to test the feasibility, acceptability, and efficacy of the telephonic MBI for pain catastrophizing in persons with SCD and chronic pain. Acceptability and feasibility were determined by assessment of recruitment, attrition, dropout, and refusal rates (including refusal reasons), along with semi-structured interviews with nine randomly selected patients at the end of study. Participants completed assessments at baseline, Week 1, 3, and 6 to assess efficacy of the intervention on decreasing pain catastrophizing and other pain-related outcomes.
Results: A telephonic MBI is feasible and acceptable for persons with SCD and chronic pain. Seventy-eight patients with SCD and chronic pain were approached, and 76% (N = 60) were enrolled and randomized. The MBI attendance rate, approximately 57% of participants completing at least four mindfulness sessions, was deemed acceptable, and participants that received the telephonic MBI described it as acceptable, easy to access, and consume in post-intervention interviews. The amount of missing data was undesirable (MBI condition, 40%; control condition, 25%), but fell within the range of expected missing outcome data for a RCT with multiple follow-up assessments. Efficacy of the MBI on pain catastrophizing could not be determined due to small sample size and degree of missing data, but trajectory analyses conducted for the MBI condition only trended in the right direction and pain catastrophizing approached statistically significance.
Conclusion: Overall results showed that at telephonic group-based MBI is acceptable and feasible for persons with SCD and chronic pain. Though the study was not able to determine treatment efficacy nor powered to detect a statistically significant difference between conditions, participants (1) described the intervention as acceptable, and (2) the observed effect sizes for the MBI condition demonstrated large effects of the MBI on pain catastrophizing, mental health, and physical health. Replication of this MBI study with a larger sample size, active control group, and additional assessments at the end of each week (e.g., Week 1 through Week 6) is needed to determine treatment efficacy. Many lessons were learned that will guide the development of future studies including which MBI strategies were most helpful, methods to encourage continued participation, and how to improve data capture.
Item Open Access Perspectives on Genetics Research and Cures for Sickle Cell Disease in Jamaica(2021) Jones, KrystinBackground: Sickle cell disease (SCD) is the most common genetic disorder of the blood. Jamaica has the highest recorded SCD prevalence in the Caribbean (0.65%). SCD treatment options are limited though new genetics research technologies such as gene editing and gene therapy show great promise as SCD cures. An ethical framework based on social and cultural contexts must inform the conduct of genetics research and the introduction of these technologies to the Jamaican SCD population. Methods: This qualitative cross-sectional study used semi-structured in-depth interviews to investigate perspectives on genetics research and cures for SCD and the social, cultural and ethical factors related to these perspectives among 10 SCD healthcare providers, 10 SCD patients and 9 parents affiliated with the Sickle Cell Unit (SCU) in Kingston Jamaica. Results: Though they expressed some skepticism, participants were optimistic about genetics research. They believed it would lead to improved SCD treatment and advance SCD knowledge. Attitudes towards genetics research also pointed to potential ethical issues regarding autonomy, confidentiality and benefit sharing. Participants also viewed SCD cures positively, though 4 patients revealed they had no interest in receiving a SCD cure. Participants also described a number of social and cultural factors such as socioeconomic issues, stigma and information seeking behavior that contextualized these perspectives. Conclusions: We propose a framework that integrates these perspectives, and the social and cultural contexts to guide SCD genetics research and the introduction of gene-based SCD cures in Jamaica. Researchers in genetics must work closely with the SCU to ensure that participants fully understand study aims and methods, and develop benefit-sharing models that will ensure that participants and the wider Jamaican SCD community benefit from research to which they contribute. As SCD gene-based technologies become more readily available in Jamaica in the long term, the local health system must prioritize related professional and public education and programming, as well as social and counselling services to adequately prepare patients and parents to receive these technologies.
Item Open Access Psychosocial Burden of Childhood Sickle Cell Disease on Family Members and Caregivers, Homa Bay, Kenya.(2019) Kuerten, Bethany GraceObjective To characterize the types and magnitude of family burden present in caregivers and families who have a child with Sickle Cell Disease (SCD) in Kenya; to identify demographic and disease-specific predictors of caregiver burden. Methods Primary caregivers (N = 103) of children diagnosed with SCD completed surveys assessing multiple domains of caregiver quality of life, parental adjustment related to child illness, mental health, and financial burden. Descriptive statistics characterize caregiver burden and linear regressions models assess associations. Results On indicators of quality of life (QOL), caregivers report problems across most domains assessed included their daily activities and their physical, social, cognitive, and emotional well-being. Daily Activities emerged as most burdensome. On indicators of parental adjustment to chronic illness, guilt and worry emerged as the largest concern, though they also experience long-term uncertainty and sorrow and anger; they reported relatively high levels of emotional resources. Financial burden was high; caregivers reported moderate to major loss in revenue and financial benefits due to the time spent caring for the child. Linear regression analyses revealed that financial burden was a significant predictor of all negative outcomes. Conclusions Results provide preliminary evidence that Kenyan caregivers of children with SCD experience difficulties across multiple domains of functioning and that financial struggles are associated with most psychosocial outcomes. Results can begin to guide intervention needs and opportunities.
Item Open Access Quality of Life and Neurocognitive Functioning in Children with Sickle Cell Disease: Investigating the Feasibility of a Computerized Cognitive Training Program(2014) Allen, Taryn MargaretChildren with sickle cell disease (SCD) have a high risk of neurocognitive impairment. No known research, however, has examined the impact of neurocognitive functioning on quality of life in this pediatric population. In addition, limited research has examined neurocognitive interventions for these children. In light of these gaps, two studies were undertaken to (a) examine the relationship between cognitive functioning and quality of life in a sample of children with SCD and (b) investigate the feasibility and preliminary efficacy of a computerized working memory training program in this population. Forty-five youth (ages 8-16) with SCD and a caregiver were recruited for the first study. Participants completed measures of cognitive ability, quality of life, and psychosocial functioning. Results indicated that cognitive ability significantly predicted child- and parent-reported quality of life among youth with SCD. In turn, a randomized-controlled trial of a computerized working memory program was undertaken. Eighteen youth with SCD and a caregiver enrolled in this study, and were randomized to a waitlist control or the working memory training condition. Data pertaining to cognitive functioning, psychosocial functioning, and disease characteristics were obtained from participants. The results of this study indicated a high degree of acceptance for this intervention but poor feasibility in practice. Factors related to feasibility were identified. Implications and future directions are discussed.
Item Open Access Stigma, Disease Self-Management, and Quality of Life in Adults with Sickle Cell Disease(2019) Bulgin, DominiqueSickle cell disease (SCD) is the most common genetic blood disorder in the United States (US) and Jamaica and primarily affects individuals of African descent. SCD can result in severe and debilitating complications, including vaso-occlusive crises and organ damage. To prevent these complications SCD requires complex self-management. SCD is associated with significantly shortened lifespans in both countries. Many personal and background factors including, perceived stigma, demographics (country, age, race, sex, socioeconomic status) and clinical (disease severity, hydroxyurea use, genotype) characteristics may influence self-management strategies and health-related quality of life (QoL) in SCD. These characteristics have not been explored fully in either country and there are many differences between countries in how SCD is managed and stigma is perceived. This dissertation aims to develop knowledge related to the relationships between SCD self-management, stigma of SCD, and health-related QoL.
A systematic literature review was conducted to appraise the current state of knowledge surrounding stigma of SCD. Conclusions from this review revealed that 1) sources of stigma were varied including institutions, healthcare systems and providers, and interpersonal relationships; 2) stigma had negative impacts on participants’ social, psychological, and physiological well-being; 3) stigma had resulted in poor patient-provider relationships and altered care-seeking behaviors in individuals with SCD, and 4) there are gaps in the literature regarding the influence of sources of stigma on self-management and QoL.
The primary study of this dissertation utilized a cross sectional, convergent parallel mixed methods design (individual interviews and self-report surveys). Participants were interviewed about disease self-management strategies and how sources of stigma influence these strategies. Demographic and clinical characteristics were assessed using questionnaires. Quantitative measures were used to assess perceived stigma [SCD Health-Related Stigma Scale (SCD-HRSS) and Measure of Sickle Cell Stigma (MoSCS)] and health-related QoL [Adult Sickle Cell Quality of Life Measures (ASCQ-Me)]. Because there were no publication using the ASCQ-Me to assess health-related QoL in adults with SCD, aside from psychometric studies, a pilot study was conducted evaluating the feasibility of using the ASCQ-Me prior to the primary dissertation study. Use of ASCQ-Me was determined to be feasible.
There were several important findings in the primary dissertation study. Employment and low disease severity were significant predictors of health-related QoL. Nonetheless, participants reported experiencing stigma from family, friends, and people in the workplace and school that impeded their access to the social support and financial resources needed to effectively self-manage. Self-management strategies were similar between the two countries with the exception of there being less opioid use and a greater focus on nutrition in Jamaica. Lastly, participants in both countries, regardless of demographic and clinical characteristics, reported perceiving stigma from healthcare settings. As a result, they altered their self-management in many ways including avoiding or delaying seeking care and pain management. Findings from this study will be used to generate hypotheses for future studies seeking to improve self-management and QoL of individuals with SCD in the presence of stigma.
Item Embargo Stroke and Neurodevelopmental Delays in Sickle Cell Disease(2023) Knight, La'Kita Maria JohnsonIn the United States of America, Sickle Cell Disease (SCD) affects 100,000 Americans, predominantly African Americans. In North Carolina (NC), there are approximately 5,578 people living with SCD, which includes both children and adults. Of those affected, 39% are 18 years of age or younger. Strokes are a major disease-related complication that children with SCD too often experience. Some complications include motor and cognitive delays, neurodevelopmental delays (NDD), decline in academic learning and attainment, poor test scores, high school dropout and/or unemployment (later in life). The purpose of this dissertation was to address the problems of stroke prevention and NDD in children with SCD. Therefore, we analyzed hydroxyurea (HU) adherence as well as transcranial Doppler (TCD) screening prevalence and proportion in a statewide Medicaid sample in an attempt to evaluate primary stroke prevention in children ages 2 to 16 years old with SCD. The purpose of this dissertation was achieved through a systematic literature review that explored the prevalence, severity, and associated risk factors for NDD in children with SCD less than or equal to 5 years. Secondary data analyses of the NC Medicaid database was used to examine the following: 1) HU adherence rates for 12- and 24-month cohorts; 2) associations of individual related sociodemographic characteristics with HU adherence; 3) the prevalence rate of children with annual TCD screenings; 4) the proportion of children with zero, 1, 2, 3 or more TCD screening claims; and 5) the prevalence rate of TCD screening claims for age, sex, residential location, and HU adherence. The methods used in the data chapters were descriptive statistics, frequencies, percentages, and chi-square was used to determine differences in HU adherence for both the 12 and 24-month cohorts (Chapter 3), Cochran-Armitage Trend Test and the Cochran-Mantel-Haenszel Test were used to evaluate the proportion of TCD claims with 2, 3, and more levels (Chapter 4), and a Poisson Regression was used to fit the effect of TCD screening claims on sociodemographic characteristics, HU adherence, and to determine the rate of TCD screenings for each of the individual predictor variables (Chapter 4). The findings from this dissertation highlighted a wide range of motor and language deficits among children ages 0 to 5 years old with SCD (Chapter 2). Other major findings included low HU utilization (Chapter 3) and low TCD screening prevalence (Chapter 4) among children ages 2 to 16 years old with SCD on NC Medicaid. Additionally, children with poor HU adherence were less likely to have TCD screening claims (Chapter 4). Therefore, tailored interventions are needed to help mitigate the problems of poor HU utilization as well as TCD screening rates among children with SCD.
Item Open Access The Omic Modifiers of Morbidity and Mortality in Sickle Cell Disease(2023) Lê, Brandon MinhSickle cell disease (SCD) is a human genetic disorder caused by a mutation in the hemoglobin beta gene, causing sickling of red blood cells (RBCs) under hypoxic conditions, vaso-occlusion and adherence to other cells and endothelium, and downstream cellular and organ damage, ultimately resulting in higher morbidity and mortality relative to healthy people. While SCD is a Mendelian disorder defined by mutation in a single gene, the clinical presentation of people with SCD is highly heterogeneous. Typical SCD complications like acute chest syndrome (ACS), pain crises, and strokes are common but not universal, the range of severity of these outcomes is highly variable (higher morbidity, but not in all people with SCD), and life expectancy is lower on average (United States: 54 years). While the hemoglobin beta locus has been comprehensively studied as the origin of SCD, study on the other genetic and “-omic” factors that modify the disease presentation are less understood. Investigation into these omic modifiers of SCD may provide insight into many potential therapeutic targets that can greatly increase the quality of life and lifespan of people with SCD.
To advance knowledge of omic modifiers of SCD, multiple approaches combining large-scale biological datasets with new methodologies and toolkits have been used to assess SCD progression across multiple facets. Whereas prior research on SCD modifiers has been performed on smaller datasets with limited genomic data, we have performed genome-wide analyses with whole-genome sequences across much larger cohorts of people with SCD. In addition, other omic datasets are addressed. Variability in methylation at CpG sites are utilized to provide measurements of biological aging in SCD that differs from normal, healthy biological aging.
Across these analyses, a more comprehensive assessment of the omic modifiers of morbidity and mortality in SCD is achieved. Further work will serve to validate the results of these analyses and recommend omic variants for investigation in therapeutic interventions.
Item Open Access The Relationship Between Support Systems and Disease Burden for Families Coping with Sickle Cell Disease in South Africa and Cameroon(2016) Wittenbrink, Brittney MichelleBackground: Sickle cell disease (SCD) is a debilitating genetic blood disorder that seriously impacts the quality of life of affected individuals and their families. With 85% of cases occurring in sub-Saharan Africa, it is essential to identify the barriers and facilitators of optimal outcomes for people with SCD in this setting. This study focuses on understanding the relationship between support systems and disease outcomes for SCD patients and their families in Cameroon and South Africa.
Methods: This mixed-methods study utilizes surveys and semi-structured interviews to assess the experiences of 29 SCD patients and 28 caregivers of people with SCD across three cities in two African countries: Cape Town, South Africa; Yaoundé, Cameroon; and Limbe, Cameroon.
Results: Patients in Cameroon had less treatment options, a higher frequency of pain crises, and a higher incidence of malaria than patients in South Africa. Social support networks in Cameroon consisted of both family and friends and provided emotional, financial, and physical assistance during pain crises and hospital admissions. In South Africa, patients relied on a strong medical support system and social support primarily from close family members; they were also diagnosed later in life than those in Cameroon.
Conclusions: The strength of medical support systems influences the reliance of SCD patients and their caregivers on social support systems. In Cameroon the health care system does not adequately address all factors of SCD treatment and social networks of family and friends are used to complement the care received. In South Africa, strong medical and social support systems positively affect SCD disease burden for patients and their caregivers. SCD awareness campaigns are necessary to reduce the incidence of SCD and create stronger social support networks through increased community understanding and decreased stigma.
Item Open Access The Role of Erythrocytic miRNA in the lifecycle of Plasmodium falciparum(2012) LaMonte, GregMalaria, caused by the apicomplexan parasite Plasmodium, is a disease which affects up to 500 million people each year. Historically, malaria infection has been combated both through the control of its vector, the Anopheles mosquito, and use of a variety of drugs, such as quinine (1800s) and chloroquine (1900s). However, with the evolution of resistance to the majority of available anti-malarial drugs, current approaches have settled upon combinatorial therapies. The most effective of these currently are ACTs (Artemisinin Combination Therapies - Artemisinin derivatives combined with a number of other drugs). However reports of Artemisinin resistance are continuing to emerge, suggesting that new approaches and increased understanding of the Plasmodium parasite is required.
Beginning with the complete sequencing of Plasmodium falciparum genome and continuing with comprehensive profiling of both the parasite's proteome and transcriptome, various genomic approaches applied in the study of malaria have led to significant new insights into the underlying biology of this parasite. While these new findings have greatly increased our understanding of genetic regulation within the malaria parasite, they largely have not yet translated into new therapeutic approaches. For this reason, considerable attention has been paid to the study of human genetic disorders which convey resistance to malaria, in the hopes that elucidating the mechanisms behind these resistances might lead to increased understanding of the parasite's biology and thus novel therapeutic approaches.
Sickle cell (HbS) erythrocytes are well known to resist malaria infection. However, the molecular basis of this resistance, long been recognized as multifactorial, contains elements which remain poorly understood. Here we show that the dysregulated erythrocytic microRNA composition, present in both HbAS and HbSS erythrocytes, is a significant determinant of resistance against the malaria parasite Plasmodium falciparum. During the intraerythrocytic lifecycle of P. falciparum, a subset of erythrocyte microRNAs translocate into the parasite. Two microRNAs, miR-451 and let-7i, were highly enriched in HbAS and HbSS erythrocytes and these miRNAs, along with miR-223, negatively regulated parasite growth. Surprisingly, we found that miR-451 and let-7i integrated into essential parasite mRNAs and, via impaired ribosomal loading, resulted in translational inhibition of the target mRNA. Hence, sickle cell erythrocytes exhibit cell-intrinsic resistance to malaria in part through an atypical microRNA activity which may present a novel host defense strategy against complex eukaryotic pathogens. In addition, the formation of these chimeric transcripts even in normal host erythrocytes illustrates a unique parasitic post-transcriptional adaptation to the host-cell environment.
Item Open Access The Sickle Cell Disease Functional Assessment (SCD-FA) tool: a feasibility pilot study.(Pilot and feasibility studies, 2022-03) Oyedeji, Charity I; Hall, Katherine; Luciano, Alison; Morey, Miriam C; Strouse, John JBackground
The life expectancy for individuals with sickle cell disease (SCD) has greatly increased over the last 50 years. Adults with SCD experience multiple complications such as cardiopulmonary disease, strokes, and avascular necrosis that lead to limitations that geriatric populations often experience. There are no dedicated instruments to measure functional decline and functional age to determine risk of future adverse outcomes in older adults with SCD. The objective of this study was to assess the feasibility of performing the Sickle Cell Disease Functional Assessment (SCD-FA).Methods
We enrolled 40 adults with SCD (20 younger adults aged 18-49 years as a comparison group and 20 older adults aged 50 years and older) in a single-center prospective cohort study. Participants were recruited from a comprehensive sickle cell clinic in an academic center in the southeastern United States. We included measures validated in an oncology geriatric assessment enriched with additional physical performance measures: usual gait speed, seated grip strength, Timed Up and Go, six-minute walk test, and 30-second chair stand. We also included an additional cognitive measure, which was the Montreal Cognitive Assessment, and additional patient-reported measures at the intersection of sickle cell disease and geriatrics. The primary outcome was the proportion completing the assessment. Secondary outcomes were the proportion consenting, duration of the assessment, acceptability, and adverse events.Results
Eighty percent (44/55) of individuals approached consented, 91% (40/44) completed the SCD-FA in its entirety, and the median duration was 89 min (IQR 80-98). There were no identified adverse events. On the acceptability survey, 95% (38/40) reported the length as appropriate, 2.5% (1/40) reported a question as upsetting, and 5% (2/40) reported portions as difficult. Exploratory analyses of physical function showed 63% (25/40) had a slow usual gait speed (< 1.2 m/s).Conclusion
The SCD-FA is feasible, acceptable, and safe and physical performance tests identified functional impairments in adults with SCD. These findings will inform the next phase of the study where we will assess the validity of the SCD-FA to predict patient-important outcomes in a larger sample of adults with SCD.Item Open Access Using Nucleic Acids to Repair β-Globin Gene Mutations(2007-05-02T17:38:03Z) Kierlin-Duncan, Monique NatashaNucleic acids are an emerging class of therapeutics with the capacity to repair both DNA and RNA mutations in clinically relevant targets. We have used two approaches, mobile group II introns and Spliceosome Mediated RNA Trans-splicing (SMaRT), to correct β-globin mutations at the DNA and RNA levels respectively. We show that the group II intron inserts site-specifically into its DNA target, even when similar targets are available. Experiments transitioning this therapeutic into mammalian cell systems are then described. We also illustrate how SMaRT RNA repair can be used to correct β-globin mutations involved in sickle cell disease and some forms of β- thalassemia. We uncovered diverse repair efficiencies when targeting sickle cell versus β- thalassemia transcripts in mammalian cells. Possible reasons for this and how it might direct target choice for the SMaRT therapeutic approach are both discussed. The therapeutic molecule in SMaRT, a Pre-Trans-splicing Molecule or PTM, is also delivered via lentivirus to erythrocyte precursors cultured from the peripheral blood of sickle cell patients. Preliminary results from these experiments are discussed.