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The dorsal region of the hippocampus (dHC) mediates many of the mnemonic functions traditionally associated with the hippocampus proper, such as spatial and episodic memory, whereas ventral hippocampus (vHC) has been extensively implicated in emotional memory and motivational processes. By contrast, the functions of the intermediate hippocampus (iHC) are far less understood. In this study, we aimed to investigate the mnemonic functions of iHC by reversibly inactivating iHC prior to testing memory in behavioral tasks dependent on the integrity of dHC, iHC, or vHC, namely, rapid place water maze, inhibitory avoidance, spontaneous alternation, and temporal ordering of odors. Given our previous findings showing that dHC and vHC are involved in mnemonic control of ingestive behavior, we also assessed the effects of iHC inactivation on sucrose intake. The results showed that pharmacological inhibition of iHC impairs rapid place water maze memory, which has been previously shown to be dependent on iHC but not dHC or vHC. iHC inactivation does not impact memory dependent on dHC (spontaneous alternation), vHC (temporal odor memory), or either dHC or vHC (inhibitory avoidance), and only modestly affects sucrose intake. These findings provide support for the involvement of iHC in mnemonic functions that are distinct from dHC and vHC and highlight the need to further advance our understanding of the functions of this hippocampal region that has been relatively understudied., (© 2024 Wiley Periodicals LLC.)

Background: Adolescence and young adulthood are vulnerable developmental periods for individuals with sickle cell disease (SCD), particularly given the impact of social inequities, challenges with transitioning to adult healthcare services, and increased risk for morbidity and mortality. Systems of power, such as institutionalized and interpersonal manifestations of bias, could impact SCD transfer and engagement in adult care through their influence on healthcare transition readiness; yet research in this area is limited., Objective: To characterize how systems of power impact transition readiness factors described in the Social-ecological Model of AYA Readiness for Transition to Promote Health Equity (SMART-E) framework at the patient, caregiver, and practitioner levels., Methods: Pediatric adolescents and young adults (AYA), transferred AYA, caregivers, and practitioners participated in semi-structured focus groups and individual interviews examining health equity and systems of power during healthcare transition. Focus groups/interviews were transcribed and coded using a deductive approach via the updated SMART-E framework., Results: Ten pediatric AYA with SCD, nine transferred AYA with SCD, eight caregivers, and nine practitioners participated in a focus group or interview. Qualitative findings across reporters emphasize the impact of systems of power (e.g., racial bias and disease stigma) on knowledge, skills and self-efficacy, beliefs and expectations, goals and motivation, and emotions and psychosocial functioning at the patient, caregiver, and practitioner levels., Conclusion: Systems of power are prevalent with respect to transition barriers for AYA with SCD and their supports. Structural, institutional, and individual factors with potential to reduce the influence of systems of power should be further identified and targeted for intervention., (© 2024 Wiley Periodicals LLC.)

Background: Suboptimal medication adherence is common across youth with chronic health conditions and may contribute to health disparities and adverse health outcomes, especially in underserved communities., Methods: Using pharmacy prescription records and guided by the World Health Organization Multidimensional Adherence Model, we examined patient-, treatment-, and health system-related factors that may affect hydroxyurea adherence in 72 youth with sickle cell disease (SCD), 10-18 years who had participated in the multisite "Hydroxyurea Adherence for Personal Best in SCD" (HABIT) feasibility (6 months) and efficacy (12 months) trials. Pharmacy data were collected from the year prior to study entry through the duration of each trial. We also examined hydroxyurea dose at baseline, prescribing patterns (hydroxyurea formulation and dose prescribed), quantity of hydroxyurea dispensed, and number of daily capsules/tablets prescribed. Data were analyzed using descriptive statistics., Results: On average, youth were prescribed 1095 ± 402 mg hydroxyurea per day, requiring ingestion of 3 or more capsules for 39.4% of youth. Frequently identified potential barriers were complex medication regimens in which dose of hydroxyurea differed by day of week (47.2%); receipt of an inadequate (< 30 days) supply of hydroxyurea from the pharmacy ≥ 3 times during record collection period (29.2%); and prescription of hydroxyurea suspension suggesting problems swallowing capsules (22.2%). In this sample, most youth were exclusively prescribed 500 mg capsules (62.5%), which was associated with complex medication regimens (RR 3.0, 95% CI 1.4-6.7). Potential barriers were common, occurred at all levels and are potentially modifiable with targeted interventions at the treatment- and health system-related levels., (© 2024 Wiley Periodicals LLC.)

Sickle cell disease (SCD) is an inherited blood disorder marked by homozygosity of hemoglobin S, which is a defective hemoglobin caused by a missense mutation in the β-globin gene. However, clinical phenotypes of SCD vary among patients. To investigate genetic variants associated with various clinical phenotypes of SCD, we genotyped DNA samples from 520 SCD subjects and used a genome-wide association study (GWAS) approach to identify genetic variants associated with phenotypic features of SCD. For HbF levels, the previously reported 2p16.1 locus (BCL11A) reached genome significance (rs1427407, P = 8.58 × 10 -10 ) in our GWAS as expected. In addition, we found a new genome-wide significance locus at 15q14 (rs8182015, P = 2.07 × 10 -8 ) near gene EMC7. GWAS of acute chest syndrome (ACS) detected a locus (rs79915189, P = 3.70 × 10 -8 ) near gene IDH2 at 15q26.1. The SNP, rs79915189, is also an expression quantitative trait locus (eQTL) of IDH2 in multiple tissues. For vasoocclusive episode (VOE), GWAS detected multiple significant signals at 2p25.1 (rs62118798, P = 4.27 × 10 -8 ), 15q26.1 (rs62020555, P = 2.04 × 10 -9 ) and 15q26.3 (rs117797325, P = 4.63 × 10 -8 ). Our findings provide novel insights into the genetic mechanisms of SCD suggesting that common genetic variants play an important role in the presentation of the clinical phenotypes of patients with SCD., (© 2024. The Author(s).)

Existing research on sensemaking in immersive analytics systems primarily focuses on understanding how users complete analysis within these systems with quantitative and qualitative datasets. However, these user studies mainly concentrate on understanding analysis styles and methodologies from a predominantly novice user study population. While this approach provides excellent initial insights into what users may do within IA systems, it fails to address how professionals may utilize an immersive analytic system for analysis tasks. In our work, we build upon an existing immersive analytics concept - "Immersive Space to Think" to understand how professional user populations differ from novice users in immersive analytic system usage. We conducted a user study with 11 professional intelligence analysts who completed three analysis sessions each. Using our results from this study, we provide deep analysis into how professional users complete sensemaking within immersive analytic systems, compare our findings to previously published findings with a novice user population, and provide insights into how to develop better IA systems to support the professional analyst's strategies within these systems.

Sickle cell disease (SCD), which occurs primarily in individuals of African descent, has been identified as a preexisting health condition for COVID-19 with higher rates of hospitalization, intensive care unit admissions, and death. National data indicate Black individuals have higher rates of vaccine hesitancy and lower COVID-19 vaccination rates. Understanding the key predictors of intention to receive a COVID-19 vaccine is essential as intention is strongly associated with vaccination behavior. This multisite study examined attitudes, beliefs, intentions to receive COVID-19 vaccines, and educational preferences among adolescents, young adults, and caregivers of children living with SCD. Participants completed an online survey between July 2021 and March 2022. Multivariate logistic regression was used to examine the association between participant age and COVID-19 vaccine attitudes, beliefs, and vaccine intentions. Of the 200 participants, 65.1% of adolescents, 62.5% of young adults, and 48.4% of caregivers intended to receive a COVID-19 vaccine for themselves or their child. Perception that the vaccine was safe was statistically significant and associated with patient and caregiver intention to receive the COVID-19 vaccine for themselves or their child. Participant age was also statistically significant and associated with the intent to get a booster for patients. Study findings highlight key concerns and influencers identified by patients with SCD and their caregivers that are essential for framing COVID-19 vaccine education during clinical encounters. Study results can also inform the design of messaging campaigns for the broader pediatric SCD population and targeted interventions for SCD subpopulations (eg, adolescents, caregivers)., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Despite disease-modifying effects of hydroxyurea on sickle cell disease (SCD), poor adherence among affected youth commonly impedes treatment impact. Following our prior feasibility trial, the "Hydroxyurea Adherence for Personal Best in Sickle Cell Treatment (HABIT)" multi-site randomized controlled efficacy trial aimed to increase hydroxyurea adherence for youth with SCD ages 10-18 years. Impaired adherence was identified primarily through flagging hydroxyurea-induced fetal hemoglobin (HbF) levels compared to prior highest treatment-related HbF. Eligible youth were enrolled as dyads with their primary caregivers for the 1-year trial. This novel semi-structured supportive, multidimensional dyad intervention led by community health workers (CHW), was augmented by daily tailored text message reminders, compared to standard care during a 6-month intervention phase, followed by a 6-month sustainability phase. Primary outcomes from the intervention phase were improved Month 6 HbF levels compared to enrollment and proportion of days covered (PDC) for hydroxyurea versus pre-trial year. The secondary outcome was sustainability of changes up to Month 12. The 2020-2021 peak coronavirus disease 2019 (COVID-19) pandemic disrupted enrollment and clinic-based procedures; CHW in-person visits shifted to virtual scheduled interactions. We enrolled 50 dyads, missing target enrollment. Compared to enrollment levels, both HbF level and PDC significantly - but not sustainably - improved within the intervention group (p = .03 and .01, respectively) with parallel increased mean corpuscular volume (MCV) (p = .05), but not within controls. No significant between-group differences were found at Months 6 or 12. These findings suggest that our community-based, multimodal support for youth-caregiver dyads had temporarily improved hydroxyurea usage. Durability of impact should be tested in a trial with longer duration of CHW-led and mobile health support., (© 2024 Wiley Periodicals LLC.)

Importance: Despite elevated health risks during young adulthood, many adolescents and young adults with serious health care needs face barriers during the transfer to an adult specialty practitioner, and health disparities may occur during the transition., Objective: To validate the content of an updated Social-Ecological Model of Adolescent and Young Adult Readiness for Transition to Promote Health Equity (SMART-E) in a group of adolescents and young adults with sickle cell disease (SCD) and their supports., Design, Setting, and Participants: Health equity framework components were reviewed. Systems of power (eg, institutional and practitioner bias) and environments or networks (eg, peer or school support) were added as SMART-E preexisting factors, and health literacy was included within readiness factors. Adolescents and young adults aged 16 to 29 years with SCD, caregivers, and practitioners participated in this convergent, mixed-methods study within Children's Hospital of Philadelphia between January and August 2022., Main Outcomes and Measures: Content validity was assessed through nominations of top 3 most important transition barriers prior to interviews and focus groups, ratings on importance of SMART-E factors (0-4 scale; ratings >2 support validity) after interviews and focus groups, nominations of 3 most important factors for transition and for health equity, and qualitative content analysis of interview transcripts., Results: The study enrolled 10 pediatric adolescents and young adults (mean [SD] age, 18.6 [2.9] years; 4 female and 6 male), 10 transferred adolescents and young adults (mean [SD] age, 22.9 [2.1] years; 8 female and 2 male), 9 caregivers (mean [SD] age, 49.8 [8.7] years; 5 female and 4 male), and 9 practitioners (mean [SD] age, 45.6 [10.5] years; 8 female and 1 male). Quantitative ratings supported the content validity of SMART-E and met established criteria for validity. Systems of power was the most endorsed transition barrier (14 of 38 participants) reported prior to interviews and focus groups. After the interview, participants endorsed all SMART-E factors as important for transition, with new factors systems of power and environments and networks rated at a mean (SD) 2.8 (1.23) and 3.1 (0.90), respectively, on a 0 to 4 scale of importance. The most important factors for transition and equity varied by participant group, with all factors being endorsed, supporting the comprehensiveness of SMART-E. Qualitative data corroborated quantitative findings, further supporting validity, and minor modifications were made to definitions., Conclusions and Relevance: SMART-E obtained initial content validation with inclusion of health equity factors for adolescents and young adults with SCD, caregivers, and practitioners. The model should be evaluated in other populations of adolescents and young adults with chronic disease.

Existing research on immersive analytics to support the sensemaking process focuses on single-session sensemaking tasks. However, in the wild, sensemaking can take days or months to complete. In order to understand the full benefits of immersive analytic systems, we need to understand how immersive analytic systems provide flexibility for the dynamic nature of the sensemaking process. In our work, we build upon an existing immersive analytic system - Immersive Space to Think, to evaluate how immersive analytic systems can support sensemaking tasks over time. We conducted a user study with eight participants with three separate analysis sessions each. We found significant differences between analysis strategies between sessions one, two, and three, which suggest that immersive space to think can benefit analysts during multiple stages in the sensemaking process.

Background: Among individuals with sickle cell disease (SCD), decreased hemoglobin is associated with lower oxygen saturation (SpO2) and increased risk of stroke, both of which are associated with lower intelligence quotient (IQ) scores. Thus, increasing hemoglobin and SpO2 in individuals with SCD may increase IQ and educational attainment., Methods: A cohort simulation model was built to determine academic performance and educational attainment based on cognitive function (measured by IQ) of a pediatric SCD cohort randomly assigned to treatment and control groups. The model contained two key stages: childhood (<10 years) and adolescence (≥10 years). In stage 1, increased hemoglobin and increased SpO2 (assigned to the treatment group) were determinants of higher IQ, prevention of IQ deterioration over time. Increased hemoglobin was also a determinant of decreased stroke risk. In stage 2, improvement in adolescent IQ as a result of treatment was a determinant of academic performance., Results: In a simulated cohort of 2000 children and adolescents with SCD (52.5% female, 50% treated), stroke incidence was predicted to be 44.4% lower among the treated group than the untreated group (4.5% versus 8.1%, respectively). The average IQ among the treated group was estimated to be 91.1 compared with 82.9 in the untreated group (a 9.9% difference; P<0.001). Finally, high school (≥12 years of education) completion rates were estimated to be 64.7% higher among the treated group: 76.1% of the treated group was projected to complete high school compared with 46.2% of the untreated group., Conclusions: Our model predicts that an average improvement in hemoglobin of 1.1 g/dL (11 g/L) among individuals with SCD may be associated with improved neurocognition and educational outcomes. These improvements may also generate benefits not captured by our model, including improved quality of life, employment, and income., Competing Interests: Joanna P. MacEwan: Current employee of Genesis Research, former employee of PRECISIONheor, a life sciences research consulting firm paid by Global Blood Therapeutics, Inc., to conduct this study; research funding from NHLBI, HRSA, PCORI, and ASH. Allison A. King: Research funding from Global Blood Therapeutics, Inc. Kim Smith-Whitley: Former employee of Global Blood Therapeutics, Inc., at the time of the study; Andy Nguyen and Irene Agodoa: Former employees at Global Blood Therapeutics, Inc., at the time of the study. Anuj Mubayi: Current employee of The Public Health Company, former employee of PRECISIONheor, a life sciences research consulting firm paid by Global Blood Therapeutics, Inc, to conduct this study. Global Blood Therapeutics, Inc. is a wholly owned subsidiary of Pfizer Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 MacEwan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Psychologists have an ethical responsibility to advance health equity and can play a significant role in improving health care experiences for families racialized as Black, including those with sickle cell disease (SCD), a group of genetic blood disorders primarily affecting communities of color. Parents of children with SCD report experiences of stigma and discrimination due to racism in the health care system. The current commentary describes the application of antiracism and participatory strategies to the research design, implementation, and dissemination of a behavioral medicine clinical trial (Engage-HU; NCT03442114) of shared decision-making (SDM) for pediatric patients with SCD, including (a) the development of a research question to promote justice for racialized groups; (b) a focus on "redressing imbalances" through SDM and a multidisciplinary, inclusive research team led by a Black psychologist; (c) community participatory approaches through the integration of stakeholder feedback across the study; and (d) centering context by attending to structural realities in response to the COVID-19 and racism pandemics. With attention to the fact that most primary caregivers of children with SCD are Black women, an intersectionality lens was applied. Implications and considerations for psychologists working to advance health equity in medical settings are also discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Sickle cell disease (SCD) requires coordinated, specialized medical care for optimal outcomes. There are no United States (US) guidelines that define a pediatric comprehensive SCD program. We report a modified Delphi consensus-seeking process to determine essential, optimal, and suggested elements of a comprehensive pediatric SCD center. Nineteen pediatric SCD specialists participated from the US. Consensus was predefined as 2/3 agreement on each element's categorization. Twenty-six elements were considered essential (required for guideline-based SCD care), 10 were optimal (recommended but not required), and five were suggested. This work lays the foundation for a formal recognition process of pediatric comprehensive SCD centers., (© 2022 Wiley Periodicals LLC.)

Background: Children with sickle cell disease (SCD) have an increased risk for gallstones due to chronic hyperbilirubinemia from hemolysis. Although gallstones are a known complication, there is variability in estimates of disease burden and uncertainty in the association between sex and gall bladder disease (GBD)., Methods: This was a retrospective cohort study of children with SCD using administrative claims data (January 1, 2014-December 31, 2018). Population-averaged multivariable panel-data logistic regression models were used to evaluate the association between GBD clinical encounters (outcome) and two exposures (age and sex). Annual GBD risk was calculated using predictive margins, adjusting for disease severity, transfusion frequency, and hydroxyurea exposure., Results: A total of 13,745 individuals (of 21,487 possible) met inclusion criteria. The population was evenly split across sex (49.5% female) with predominantly Medicaid insurance (69%). A total of 946 individuals (6.9%) had GBD, 432 (3.1%) had a gallstone complication, and 487 (3.5%) underwent cholecystectomy. The annual risk of GBD rose nonlinearly from 1 to 5% between ages 1 and 19 years with no difference between males and females. Cholecystectomy occurred primarily in individuals with GBD (87%), and neither age nor sex was associated with cholecystectomy in this population. High disease severity (compared with low) more than doubled the annual risk of GBD at all ages., Conclusions: GBD is associated with age but not sex in children with SCD. Neither age nor sex is associated with risk of cholecystectomy. High disease severity increases the rate of GBD at all ages., (© 2022 Wiley Periodicals LLC.)

Background: Adolescent and young adult (AYA) women with sickle cell disease (SCD) have increased pregnancy-related health risks and are prescribed potentially teratogenic medications, yet limited data are available regarding pediatric SCD provider contraceptive practices. We aimed to assess pediatric hematology providers' beliefs, practices, motivators, and barriers for providing contraceptive care to female AYAs with SCD., Methods: Guided by the Health Belief Model (HBM), we developed a 25-question, web-based survey to assess practices. Survey links were distributed nationwide to pediatric SCD and/or general hematology providers through their publicly available emails and by request to directors of U.S.-accredited Pediatric Hematology-Oncology fellowship programs for distribution to their SCD providers. Data analysis included descriptive statistics, chi-square analysis, and logistic regression., Results: Of 177 respondents, 160 surveys meeting inclusion criteria were analyzed. Most providers reported counseling (77.5%) and referring female AYA patients for contraception (90.8%), but fewer reported prescribing contraception (41.8%). Proportionally fewer trainees provided counseling compared with established providers (54% vs. 85%, p < .001), with a similar trend for prescribing (p = .05). Prescription practices did not differ significantly by provider beliefs regarding potential teratogenicity of hydroxyurea. Key motivators included patient request and disclosure of sexual activity. Key barriers included inadequate provider training, limited visit time, and perceived patient/parent interest., Conclusion: Provider contraceptive practices for female AYAs with SCD varied, especially by provider status. Health beliefs regarding teratogenic potential of hydroxyurea did not correlate with contraceptive practices. Clinical guidelines, provider training, and patient/parent decision-making tools may be tested to assess whether provider contraceptive practices could be improved., (© 2022 Wiley Periodicals LLC.)

Youth with sickle cell disease (SCD) and their caregivers are susceptible to stress and depression, perhaps exacerbated by pandemic-associated health and economic concerns. Most of the 50 youth-caregiver dyads enrolled in the multisite trial, Hydroxyurea Adherence for Personal Best in Sickle Cell Treatment (HABIT), took an online survey of self-reported mental health symptoms and food insecurity during the 2020 COVID-19 pandemic. Compared to largely pre-pandemic results, prevalence of mental health symptoms in dyad members appeared to have shifted: fewer youth and more caregivers were affected during the pandemic; many of both groups lacked optimism. Pandemic/post-pandemic screening of youth with SCD for mental health symptoms and food insecurity appears warranted., (© 2022 Wiley Periodicals LLC.)

Background: Sickle cell disease (SCD) is a devastating, multisystemic disorder that affects millions of people worldwide. The earliest clinical manifestations of SCD can affect infants as young as 6 months of age, and pediatric patients are at risk for acute and life-threatening complications. Early intervention with treatments that target the underlying pathophysiological mechanism of SCD, sickle hemoglobin (HbS) polymerization, are expected to slow disease progression and circumvent disease-associated morbidity and mortality., Procedure: The HOPE-KIDS 1 trial (NCT02850406) is an ongoing four-part, phase 2a, open-label, single- and multiple-dose study to evaluate the pharmacokinetics, efficacy, and safety of voxelotor-a first-in-class HbS polymerization inhibitor-in patients aged 6 months to 17 years with SCD. Initial findings from a cohort of 45 patients aged 4 to 11 years who received voxelotor treatment for up to 48 weeks are reported., Results: Hemoglobin (Hb) response, defined as a >1.0 g/dl increase from baseline, was achieved at week 24 by 47% (n = 16/34) of patients with Hb measurements at baseline and week 24. At week 24, 35% (n = 12/34) and 21% (n = 7/34) of patients had a >1.5 g/dl increase and a >2.0 g/dl increase from baseline in Hb concentration, respectively. Concurrent improvements in hemolytic markers were observed. Voxelotor was well tolerated in this young cohort, with no newly emerging safety signals., Conclusions: Based on its mechanism as an HbS polymerization inhibitor, voxelotor improves Hb levels and markers of hemolysis and has the potential to mitigate SCD-related complications; these results support its use in patients aged ≥4 years., (© 2022 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Objective: Asthma is a recognized comorbidity in children with sickle cell disease (SCD). It increases the risk of acute chest syndrome (ACS), vaso-occlusive episodes, and early mortality. We aim to determine whether evaluation and management of children with SCD and asthma by a pulmonologist reduce rate of asthma exacerbation and ACS., Methods: The study included 192 patients with SCD (0-21 years) followed at Children's Hospital of Philadelphia Hematology between January 1, 2015, and December 31, 2018, with a diagnosis of asthma, wheeze, or cough. Patients were placed in two groups: those evaluated by a pulmonologist (SCD-A-P) and those not (SCD-A). Rates of emergency department (ED) visits and hospitalizations for asthma exacerbation and ACS were compared between groups and over time., Results: SCD-A-P patients (n = 70) were predominantly SCD type SS with lower hemoglobin and hematocrit compared to SCD-A patients (n = 122). SCD-A-P started with a higher average rate of hospital visits for asthma exacerbation and ACS per year (2.69 [1.02-4.37]) compared to SCD-A (0.43 [0.24-0.63]), (p < 0.001). For SCD-A-P patients with at least one hospital visit (n = 48), the average rate decreased from 3.93 (1.57-6.29) to 0.85 (0.48-1.23) following pulmonary consultation (p = 0.014) and was comparable to the SCD-A rate by study end., Conclusion: SCD-A-P was mainly SCD type SS and had higher ED/hospitalization rates for asthma exacerbation and ACS compared to SCD-A, but the rates significantly decreased following pulmonology consultation. These findings support the pulmonologist's role in the multidisciplinary care of SCD patients and highlight the need for evidence-based asthma guidelines for children with SCD., (© 2022 Wiley Periodicals LLC.)

Objectives: Females with sickle cell disease now have a life expectancy that extends well into and beyond their reproductive years. Pregnancy and childbirth are accompanied by high morbidity and mortality in this population, rendering contraception a critical part of their health care., Study Design: We approached adult female patients of the Hospital of the University of Pennsylvania hematology clinic who were of reproductive age (ages 18-45) and carried a diagnosis of sickle cell disease. We evaluated contraceptive method uptake and method characteristic preferences, as well as other reproductive history, and compared contraceptive uptake rates to that from female respondent data from the National Survey of Family Growth (2017-2019)., Results: Of 95 eligible patients, we completed surveys with 48 participants (response rate of 51%). Over half (n = 27, 56%) of participants were not currently using any form of contraception-double the rate of the general United States population (25%). The most common contraceptives currently used were the depot medroxyprogesterone (DMPA) injection (n = 6, 13%) and the progestin intrauterine device (IUD) (n = 6, 13%). DMPA uptake was significantly higher, and permanent contraceptive and oral contraceptive pill uptake significantly lower, among these participants with sickle cell disease compared to the general United States population. Participants' preferred contraceptive characteristics included effectiveness (n = 39, 81%), control over when to use the contraceptive (n = 39, 81%), and lack of side effects (n = 38, 79%)., Conclusions: Contraceptive uptake was significantly lower and method mix different among females with sickle cell disease compared to the general United States population. Further research is needed on contraceptive safety, non-contraceptive benefits, and contraceptive decision-making for females with sickle cell disease., Implications: This study sheds light on the contraceptive choices and preferences of females with sickle cell disease, who are at disproportionate risk for pregnancy complications. In order to maximize the reproductive health of females with sickle cell disease, we must consider how their disease interacts with contraception and better understand how they approach contraceptive decision-making., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Mental health treatment of juvenile offenders and undocumented immigrant youth in detention provides a unique opportunity for treatment providers. Although the work may be challenging, the clinical needs and opportunities for early and meaningful interventions are significant. One of the best clinical experiences a psychiatrist can have is working with extremely high-risk youth to help them find safer and better developmental pathways. Few settings can offer such an opportunity to leverage clinical skills to improve the lives and futures of children and adolescents as are afforded to those professionals lucky enough to work in juvenile justice settings., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

There is an immediate need to address long-standing questions about the reproductive health of girls and women with sickle cell disease (SCD). There are many SCD-related reproductive risks and uncertainties across girls' and women's reproductive life span, with particularly outstanding concerns about menstruation, contraception, fertility and pregnancy. Extant literature addressing women's reproductive health topics is mostly descriptive; there are few high-quality interventional studies. In 2020, the Centers for Disease Control and Prevention and the Foundation for Women and Girls with Blood Disorders convened an expert panel to assess the knowledge gaps in women's reproductive health in SCD. The panel identified significant limitations to clinical care due to the need for research. The panel also identified prominent barriers to research and care. In this report, we frame these issues, providing a roadmap for investigators, funding agencies, and policy makers to advance care for girls and women with SCD., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Sickle cell trait (SCT), a commonly asymptomatic condition, has many associated clinical complications that upon presentation, can be very difficult to attribute to SCT. The effects of SCT on the spleen, for example, are not completely understood, though there have been a number of case reports detailing related complications in diverse populations. Our objective was to perform the first comprehensive case report review of splenic infarction in SCT patients to highlight the relevance of this seemingly rare condition. We conducted an extensive literature search reviewing case reports and case series of acute splenic infarctions from 1970 to 2020. This comprehensive search resulted in 54 articles with a total of 85 individuals. The ages ranged from 7 to 65, 12% were female. Individuals were of African-American (26%), European (16%), South Asian (13%), Middle Eastern (7%), Latin American (7%), North or East African (4%), Mediterranean (4%), West African (1%), and unknown (22%) origins. Although splenic infarct in SCT patients has been associated with high altitudes, 39% of cases reporting altitude occurred below 3000 m. Among cases where HbS values were recorded, 88% occurred in individuals with HbS levels higher than 35%, suggesting that high HbS values may be a risk factor for splenic infarction. Our findings indicate that splenic infarct occurs across a wide range of demographic populations and environmental settings. While our understanding of SCT evolves, the findings here suggest that future advances in research and healthcare could benefit more from real-time surveillance and registry initiation for various SCT outcomes such as splenic infarct.

Background: Sickle cell anemia (SCA) is a genetic blood disorder that puts children at a risk of serious medical complications, early morbidity and mortality, and high health care utilization. Until recently, hydroxyurea was the only disease-modifying treatment for this life-threatening disease and has remained the only option for children younger than 5 years. Evidence-based guidelines recommend using a shared decision-making (SDM) approach for offering hydroxyurea to children with SCA (HbSS or HbS/β0 thalassemia) aged as early as 9 months. However, the uptake remains suboptimal, likely because caregivers lack information about hydroxyurea and have concerns about its safety and potential long-term side effects. Moreover, clinicians do not routinely receive training or tools, especially those that provide medical evidence and consider caregivers' preferences and values, to facilitate a shared discussion with caregivers., Objective: The aim of this study is to understand how best to help parents of young children with sickle cell disease and their clinicians have a shared discussion about hydroxyurea (one that considers medical evidence and parent values and preferences)., Methods: We designed our study to compare the effectiveness of two methods for disseminating hydroxyurea guidelines to facilitate SDM: a clinician pocket guide (ie, usual care) and a clinician hydroxyurea SDM toolkit (H-SDM toolkit). Our primary outcomes are caregiver reports of decisional uncertainty and knowledge of hydroxyurea. The study also assesses the number of children (aged 0-5 years) who were offered and prescribed hydroxyurea and the resultant health outcomes., Results: The Ethics Committee of the Cincinnati Children's Hospital Medical Center approved this study in November 2017. As of February 2021, we have enrolled 120 caregiver participants., Conclusions: The long-term objective of this study is to improve the quality of care for children with SCA. Using multicomponent dissemination methods developed in partnership with key stakeholders and designed to address barriers to high-quality care, caregivers of patients with SCA can make informed and shared decisions about their health., Trial Registration: ClinicalTrials.gov NCT03442114; https://clinicaltrials.gov/ct2/show/NCT03442114., International Registered Report Identifier (irrid): DERR1-10.2196/27650., (©Anna M Hood, Heather Strong, Cara Nwankwo, Yolanda Johnson, James Peugh, Constance A Mara, Lisa M Shook, William B Brinkman, Francis J Real, Melissa D Klein, Rogelle Hackworth, Sherif M Badawy, Alexis A Thompson, Jean L Raphael, Amber M Yates, Kim Smith-Whitley, Allison A King, Cecelia Calhoun, Susan E Creary, Connie M Piccone, Aimee K Hildenbrand, Steven K Reader, Lynne Neumayr, Emily R Meier, Amy E Sobota, Sohail Rana, Maria Britto, Kay L Saving, Marsha Treadwell, Charles T Quinn, Russell E Ware, Lori E Crosby. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 21.05.2021.)

Ongoing clinical trials for treatment of beta-globinopathies by gene therapy involve the transfer of the beta-globin gene, which requires integration of three to four copies per genome in most target cells. This high proviral load may increase genome toxicity, potentially limiting the safety of this therapy and relegating its use to total body myeloablation. We hypothesized that introducing an additional hypersensitive site from the locus control region, the complete sequence of the second intron of the beta-globin gene, and the ankyrin insulator may enhance beta-globin expression. We identified a construct, ALS20, that synthesized significantly higher adult hemoglobin levels than those of other constructs currently used in clinical trials. These findings were confirmed in erythroblastic cell lines and in primary cells isolated from sickle cell disease patients. Bone marrow transplantation studies in beta-thalassemia mice revealed that ALS20 was curative at less than one copy per genome. Injection of human CD34 + cells transduced with ALS20 led to safe, long-term, and high polyclonal engraftment in xenograft experiments. Successful treatment of beta-globinopathies with ALS20 could potentially be achieved at less than two copies per genome, minimizing the risk of cytotoxic events and lowering the intensity of myeloablation., (Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Little is known about the level of burnout among program administrators (PAs) in medical education and its impact on the trainee environment., Objective: To investigate variations in burnout levels over a 1-year period among a national cohort of PAs and examine any associations between perceived support and isolation., Design: A 1-year longitudinal study conducted to assess burnout levels among PAs across the USA. The Copenhagen Burnout Inventory (score range, 0-100) was used to measure burnout over one academic year (July 2017-June 2018). The generalized estimating equations model was used to measure changes in burnout levels from the start of the academic year. To explore the differences in burnout scores across question response levels, a one-way ANOVA test was utilized and reported as least squares means ± SD., Participants: Individuals who self-identified as PAs in a graduate medical education training program. Among the 1084 persons nationwide who expressed interest, 904 (83%) completed the baseline survey; 29 of the 42 (69%) local administrators completed the survey. "Clients" defined as interns, residents/fellows, and medical students., Main Measures: Change in burnout score using the validated tool. Hypothesis formulated prior to data collection., Key Results: Among the 931 participants, the 3rd quarter (March 2018) marked the lowest average personal burnout score (change from the start of academic year, - 3.67; p < 0.001, 95% CI - 5.77 to - 1.58) and work-related burnout score (change, - 3.03; p < 0.001, 95% CI - 5.01 to - 1.06). Client-related burnout was the lowest in September 2017 (change, - 1.46; p = 0.491; 95% CI - 3.54 to 0.62). June 2018: those who strongly agreed to feeling isolated in their current position had an increased personal (69.1 ± 18.4 SD), work-related (72.5 ± 20.8 SD), and client-related (42.3 ± 23.7 SD) burnout score., Conclusions: PA burnout levels fluctuate over the academic year and are shown to increase as feelings of isolation grow.

Introduction: No study determined if vitamin D supplementation improves health-related quality of life (HRQL) using pediatric Patient-Reported Outcomes Measurement Information System or physical functioning in type SS sickle cell disease (HbSS)., Method: Subjects with HbSS (n = 21) and healthy subjects (n = 23) were randomized to daily oral doses (4,000 vs. 7,000 IU) of cholecalciferol (vitamin D 3 ) and evaluated at 6 and 12 weeks for changes in serum 25 hydroxyvitamin D (25(OH)D), HRQL, and physical functioning., Results: In subjects with HbSS, significant reductions in pain, fatigue, and depressive symptoms and improved upper-extremity function were observed. In healthy subjects, significant reductions in fatigue and improved upper-extremity function were observed. Significant improvements in peak power and dorsiflexion isometric maximal voluntary contraction torques were observed in both groups. In subjects with HbSS, improved plantar flexion isometric maximal voluntary contraction torques were observed. Both groups saw significant improvement in their total Bruininks-Oseretsky Test of Motor Proficiency score., Discussion: Daily high-dose vitamin D supplementation for African American children with and without HbSS improved HRQL and physical performance., (Copyright © 2020 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.)

Background: Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy associated with morbidity and mortality. We sought to understand family planning intentions of parents of young children with SCD including the awareness of three reproductive options (adoption, in vitro fertilization with egg/sperm donation [IVFD], in vitro fertilization [IVF] with preimplantation genetic testing [IVF/PGT]) to decrease the risk of having a child with SCD., Procedure: Qualitative, semistructured, one-on-one interviews with 18 female parents of young children with SCD at an urban, tertiary care pediatric hospital., Results: Half of the parents knew their hemoglobinopathy status or their partner's status before pregnancy. Eight parents chose to have no further children because of fear of SCD in another child. Awareness of reproductive options prior to study enrollment was limited. After brief introduction, 7 parents would consider adoption, 2 IVFD, and 10 IVF/PGT. Desire for a biological child, fear of parental jealousy, ethical or religious considerations, and cost affected the acceptability of these options. Participants universally wanted information about reproductive options available to others prior to pregnancy., Conclusions: There is limited awareness and variable acceptability of alternative reproductive options available to decrease the risk of a future child having SCD. Participants universally endorsed the need for education regarding hemoglobinopathy status, SCD, and reproductive options prior to pregnancy because for many participants having a child with SCD affected their reproductive intentions. Educational interventions to ensure informed reproductive decision making should be sensitive to desires for a biological child, and ethical and financial considerations., (© 2020 Wiley Periodicals, Inc.)

Suboptimal vitamin A status (serum retinol <30 µg/dL) is associated with poor clinical outcomes in children with the hemoglobin-SS disease (HbSS), and supplementation with the recommended daily allowance of retinol is ineffective in improving vitamin A status. In a single-center randomized blinded dose-finding pilot study, we compared vitamin A and nutritional status in children with HbSS to healthy children and explored the impact of high-dose supplementation on the primary outcome serum vitamin A status. Exploratory outcomes included hematologic, nutritional, immunologic, and muscle function status in children with HbSS. A mixed-effects linear regression model evaluated associations between vitamin A dose, serum retinol, and exploratory outcomes. Twenty healthy children participated, and 22 subjects with HbSS were randomized to oral 3000 or 6000 IU/d retinol for 8 weeks; 21 subjects completed all evaluations. Serum retinol, growth, and nutritional status were all suboptimal in HbSS subjects at baseline, and supplementation did not change vitamin A status. Fetal hemoglobin (Δ=2.5, 95% confidence interval [CI], 0.5-4.3), mean corpuscular volume (Δ=2.7, 95% CI, 0.7-4.7), mean corpuscular hemoglobin (Δ=1.4, 95% CI, 0.5-2.3), and mean corpuscular hemoglobin concentration (Δ=0.5, 95% CI, 0.1-0.9) all improved with supplementation. Mild improvements in erythrocyte indices, growth status, and muscle function occurred independent of hydroxyurea use.

Pregnancy in women with sickle cell disease (SCD) is associated with increased maternal and fetal morbidity and mortality. Outcomes vary widely owing to methodological limitations of clinical studies, but overall, hypertensive disorders of pregnancy, venothromboembolism, poor fetal growth, and maternal and perinatal mortality are increased globally. Few therapeutic interventions have been explored other than prophylactic and selective transfusion therapy. Unfortunately, existing data are limited, and it remains unclear whether prophylactic use of chronic transfusions will improve pregnancy outcomes. Management of pregnant women with SCD is best accomplished with a multidisciplinary team that includes a sickle cell expert and an obstetrician familiar with high-risk pregnancies. Women with SCD should have individualized care plans that outline management of acute pain and guidelines for transfusion therapy. Neonates require close monitoring for neonatal abstinence syndrome and hemolytic disease of the newborn. Ideally all young women with SCD will have a "reproductive life plan" developed as a component of preconception counseling and health promotion. Research leading to improved pregnancy management focused on diminishing adverse maternal and neonatal outcomes is overdue. International collaborations should be considered to improve subject recruitment and foster timely completion of clinical trials. Additional therapeutic interventions outside of transfusion therapy should be explored., Competing Interests: Conflict-of-interest disclosure: K.S.-W. is on advisory committees for Pfizer, Global Blood Therapeutics (no honoraria), and Celgene (honorarium); has provided nonpaid expert testimony; and is a Sickle Cell Disease Association of America, Inc. Board Member., (© 2019 by The American Society of Hematology. All rights reserved.)

Although elevated right ventricular pressure and left ventricular diastolic dysfunction measured by echocardiogram are independent predictors of death in adults with sickle cell disease (SCD), the utility of routine echocardiographic screening in the pediatric population is controversial. We performed a 3-year retrospective review of children ≥ 10 years of age with SCD who underwent an outpatient transthoracic echocardiogram as part of a screening program. Of 172 patients referred for screening, 105 (61%) had a measurable tricuspid regurgitation jet velocity (TRV): median 2.4 m/s (IQR 2.3-2.5). Elevated right ventricular (RV) pressure (TRV ≥ 2.5 m/s, 25 mmHg), documented in 30% (32/105), was significantly associated with chronic transfusion therapy and elevated lactate dehydrogenase. Left ventricle (LV) dilation, documented in 25% (44/172), was significantly associated with lower hemoglobin, and higher reticulocyte count, lactate dehydrogenase level, and bilirubin level. There was no association between elevated right ventricular pressure or left ventricle dilation and indices of biventricular systolic or diastolic function. The one death in the cohort during the study period had normal echocardiographic findings. In conclusion, mild RV pressure elevation and LV dilation in children with SCD is associated with abnormal laboratory markers of disease severity, but not with ventricular dysfunction over the 3-year study period.

In this study, we aimed to identify common genetic components during stress response responsible for crosstalk among stresses, and to determine the role of differentially expressed genes in Arabidopsis-Botrytis cinerea interaction. Of 1,554 B. cinerea up-regulated genes, 24%, 1.4% and 14% were induced by biotic, abiotic and hormonal treatments, respectively. About 18%, 2.5% and 22% of B. cinerea down-regulated genes were also repressed by the same stress groups. Our transcriptomic analysis indicates that plant responses to all tested stresses can be mediated by commonly regulated genes; and protein-protein interaction network confirms the cross-interaction between proteins regulated by these genes. Upon challenges to individual or multiple stress(es), accumulation of signaling molecules (e.g. hormones) plays a major role in the activation of downstream defense responses. In silico gene analyses enabled us to assess the involvement of RAP2.4 (related to AP2.4) in plant immunity. Arabidopsis RAP2.4 was repressed by B. cinerea, and its mutants enhanced resistance to the same pathogen. To the best of our knowledge, this is the first report demonstrating the role of RAP2.4 in plant defense against B. cinerea. This research can provide a basis for breeding programs to increase tolerance and improve yield performance in crops.

Uptake of prenatal genetic testing (PGT) is low among those with sickle cell disease (SCD). This study evaluated the association of knowledge and attitudes towards prenatal genetic counseling (PGC), awareness of posttesting intervention options and omission bias with attitudes towards PGT. In addition, we explored changes among knowledge, attitudes, and awareness of options following exposure to an educational, clinical vignette among parents of children with SCD. Parents (n=44) completed a questionnaire and an educational, clinical vignette presenting a detailed account of a pregnant woman with sickle cell trait seeking PGT and PGC was read to each participant. t Tests, Spearman correlations, multivariable regressions, and moderation/mediation analyses were used. More positive attitudes towards PGC (P=0.01), lesser tendency of omission bias (P<0.01) and private insurance (P=0.04) were significant correlates of more positive attitudes towards PGT. Omission bias mediated the relationship of attitudes towards PGC and attitudes towards PGT (95% confidence interval: 0.13, 3.03). Awareness of options (P=0.02), knowledge of PGC (P=0.01) and knowledge of PGT (P=0.01) significantly improved after exposure to the clinical vignette. Patients and families with SCD can benefit from education about the importance of prenatal diagnosis to improve attitudes, address omission bias and promote more informed decisions of PGT.

Sickle cell disease (SCD) is an inherited blood disorder most common among African American and Hispanic American persons. The disease can cause substantial, long-term, and costly health problems, including infections, stroke, and kidney failure, many of which can reduce life expectancy. Disparities in receiving health care among African Americans and other racial/ethnic minority groups in the United States are well known and directly related to poor outcomes associated with SCD. As an orphan disease-one that affects <200 000 persons nationwide-SCD does not receive the research funding and pharmaceutical investment directed to other orphan diseases. For example, cystic fibrosis affects fewer than half the number of persons but receives 3.5 times the funding from the National Institutes of Health and 440 times the funding from national foundations. In this review, we discuss the health inequities affecting persons with SCD, describe programs intended to improve their care, and identify actions that could be taken to further reduce these inequities, improve care, control treatment costs, and ease the burden of disease.

Background: Hydroxyurea (HU) is recommended as standard practice for youth with sickle cell disease (SCD). Yet, despite its efficacy, HU adherence in adolescents and young adults is often poor. Poor medication adherence increases disease burden, healthcare cost and widens health disparities. Adolescence is a critical time to improve adherence through improved chronic disease self-management. This study aims to test the efficacy of an intervention delivered to youth/parent dyads by community health workers (CHWs), augmented by tailored text messages on HU adherence (primary outcome). Secondary outcomes are intervention sustainability, youth health-related quality of life, self-management responsibility concordance, acute hospital use and self-reported disease symptoms., Methods: Hydroxyurea Adherence for Personal Best in Sickle Cell Disease, "HABIT," is a 12 month multi-center randomized controlled trial. One hundred four youth, 10 to 18 years of age prescribed HU who meet eligibility criteria, enrolled with their parent as dyads, will be randomized 1:1 to either the HABIT intervention or to usual clinical care plus education handouts. All subjects will complete clinic visits at months 0, 2, 4, 6 (efficacy component), 9 and 12 (sustainability component) for assessment of HbF biomarker, other hematologic parameters, and to complete questionnaires. In addition, dyads assigned to the HABIT intervention will work with CHWs to identify a daily habit (e.g., brushing teeth) on which to build a HU adherence habit. Tailored daily text message reminders to support the habit will be developed by the dyad in collaboration with the CHWs and sent to parent and youth. At the 6 month visit, the intervention will end and the sustainability portion of the trial will begin. All data analyses will be based on intention to treat with all randomized subjects included in the analyses., Discussion: Prior retrospective studies demonstrate that a majority of adolescents are poorly adherent to HU. If efficacious, the HABIT intervention has the potential to improve the lives of youth with SCD., Trial Registration: Clinicaltrials.gov NCT03462511 . Registered March 6, 2018, last updated July 26, 2019.

Background: Pulmonary complications of sickle cell disease (SCD) are diverse and encompass acute and chronic disease. The understanding of the natural history of pulmonary complications of SCD is limited, no specific therapies exist, and these complications are a primary cause of morbidity and mortality. Methods: We gathered a multidisciplinary group of pediatric and adult hematologists, pulmonologists, and emergency medicine physicians with expertise in SCD-related lung disease along with an SCD patient advocate for an American Thoracic Society-sponsored workshop to review the literature and identify key unanswered clinical and research questions. Participants were divided into four subcommittees on the basis of expertise: 1 ) acute chest syndrome, 2 ) lower airways disease and pulmonary function, 3 ) sleep-disordered breathing and hypoxia, and 4 ) pulmonary vascular complications of SCD. Before the workshop, a comprehensive literature review of each subtopic was conducted. Clinically important questions were developed after literature review and were finalized by group discussion and consensus. Results: Current knowledge is based on small, predominantly observational studies, few multicenter longitudinal studies, and even fewer high-quality interventional trials specifically targeting the pulmonary complications of SCD. Each subcommittee identified the three or four most important unanswered questions in their topic area for researchers to direct the next steps of clinical investigation. Conclusions: Important and clinically relevant questions regarding sickle cell lung disease remain unanswered. High-quality, multicenter, longitudinal studies and randomized clinical trials designed and implemented by teams of multidisciplinary clinician-investigators are needed to improve the care of individuals with SCD.

Background: Little is known about the level of burnout among program administrators (PAs) working in graduate medical education., Objective: We created a national database with baseline burnout data for PAs from residency and fellowship programs, including intention to leave their current positions., Methods: A cross-sectional study was conducted in July 2017 to assess levels of burnout in a national cohort of PAs, who were largely members of online specialty forums. The Copenhagen Burnout Inventory (CBI) was used to measure burnout. Univariate analysis produced descriptive statistics for CBI. We performed a 2-sample t test to measure differences in average burnout scores for those who had thoughts of resigning from their positions and those who had not., Results: Of the approximately 10 205 national PAs, we sampled 1126 (11%). Of the 1126 individuals who received the study information, 931 (83%) completed the baseline survey. Total mean scores for all subscales were elevated (personal: 53.7, SD 21.4; work-related: 52.0, SD 22; and client-related: 30.6, SD 20.8; each scale ranged from 0, low, to 100, high). Burnout scores differed between those contemplating leaving their jobs and those who were not, across all subscales of CBI, including personal (64.2 versus 42.4, -24.18 to -19.44 confidence interval [CI]), work-related (63.5 versus 39.7, -26.12 to -21.35 CI), and client-related (36.6 versus 24.2, -14.95 to -9.84 CI; P < .0001 for all)., Conclusions: In this national survey of PAs, burnout scores measured by the CBI were higher among those who had considered leaving their positions., Competing Interests: Conflict of interest: The authors declare they have no competing interests.

β-thalassemia is a disorder caused by altered hemoglobin protein synthesis and affects individuals worldwide. Severe forms of the disease, left untreated, can result in death before the age of 3 years (1). The standard of care consists of chronic and costly palliative treatment by blood transfusion combined with iron chelation. This dual approach suppresses anemia and reduces iron-related toxicities in patients. Allogeneic bone marrow transplant is an option, but limited by the availability of a highly compatible HSC donor. While gene therapy is been explored in several trials, its use is highly limited to developed regions with centers of excellence and well-established healthcare systems (2). Hence, there remains a tremendous unmet medical need to develop alternative treatment strategies for β-thalassemia (3). Occurrence of aberrant splicing is one of the processes that affects β-globin synthesis in β-thalassemia. The (C>G) IVS-2-745 is a splicing mutation within intron 2 of the β-globin gene. It leads to an aberrantly spliced mRNA that incorporates an intron fragment. This results in an in-frame premature termination codon that inhibits β-globin production. Here, we propose the use of uniform 2'-O-methoxyethyl (2'-MOE) splice switching oligos (SSOs) to reverse this aberrant splicing in the pre-mRNA. With these lead SSOs we show aberrant to wild type splice switching. This switching leads to an increase of adult hemoglobin (HbA) up to 80% in erythroid cells from patients with the IVS-2-745 mutation. Furthermore, we demonstrate a restoration of the balance between β-like- and α-globin chains, and up to an 87% reduction in toxic α-heme aggregates. While examining the potential benefit of 2'-MOE-SSOs in a mixed sickle-thalassemic phenotypic setting, we found reduced HbS synthesis and sickle cell formation due to HbA induction. In summary, 2'-MOE-SSOs are a promising therapy for forms of β-thalassemia caused by mutations leading to aberrant splicing.

Background: Although sickle cell trait (SCT) is largely a benign carrier state, it may increase risk for certain clinical outcomes., Purpose: To evaluate associations between SCT and clinical outcomes in children and adults., Data Sources: English-language searches of PubMed, CINAHL, the Cochrane Library, Current Contents Connect, Scopus, and Embase (1 January 1970 to 30 June 2018) and bibliographies of review articles., Study Selection: Observational controlled studies (published in English) in children or adults that examined an association between SCT and any of 24 clinical outcomes specified a priori in the following 6 categories: exertion-related injury; renal, vascular, pediatric, and surgery- or trauma-related outcomes; and overall mortality., Data Extraction: A single reviewer extracted study data, which was checked by another; 2 reviewers independently assessed study quality; and strength of evidence was assessed by consensus., Data Synthesis: Of 7083 screened studies, 41 met inclusion criteria. High-strength evidence supported a positive association between SCT and risk for pulmonary embolism, proteinuria, and chronic kidney disease. Moderate-strength evidence supported a positive association between SCT and exertional rhabdomyolysis and a null association between SCT and deep venous thrombosis, heart failure or cardiomyopathy, stroke, and pediatric height or weight. Absolute risks for thromboembolism and rhabdomyolysis were small. For the remaining 15 clinical outcomes, data were insufficient or strength of evidence was low., Limitation: Publication bias was possible, and high-quality evidence was scant., Conclusion: Sickle cell trait is a risk factor for a few adverse health outcomes, such as pulmonary embolism, kidney disease, and exertional rhabdomyolysis, but does not seem to be associated with such complications as heart failure and stroke. Insufficient data or low-strength evidence exists for most speculated complications of SCT., Primary Funding Source: National Human Genome Research Institute.

Although musculoskeletal pain in patients with sickle cell disease (SCD) is most frequently the result of vaso-occlusive episodes, clinicians often consider other etiologies including osteomyelitis, avascular necrosis, and trauma. In this study, we report the case of a young female with SCD with hip and back pain secondary to a nontraumatic iliopsoas periosteal hematoma with evidence of adjacent bone infarction. The pathophysiology, diagnostic considerations, and management of periosteal hematomas in SCD are reviewed. This case highlights the need for recognition of unusual causes of musculoskeletal pain in SCD., (© 2018 Wiley Periodicals, Inc.)

In African-American children aged 5 to 17 years with and without type SS sickle cell disease (SCD-SS), dominant hand maximal handgrip strength, peak power, and plantar flexion isometric maximal voluntary contraction (MVC) torque were compared with adjustments for body size and composition. Children with SCD-SS (n=21; age, 11±1 y) compared with healthy control children (n=23; 10±1 y) did not differ by age, sex, or maturation stage, but had significantly lower Z scores for height, weight, body mass index, arm circumference, upper arm muscle area, and lean mass-for-height. Children with SCD-SS had significantly lower unadjusted handgrip strength (16±2 vs. 23±2 kg, P<0.01), peak power (1054±107 vs. 1488±169 W, P<0.04) and MVC torques at 2 angles (10 degrees: 27±3 vs. 42±5 Nm; 20 degrees: 21±3 vs. 34±4 Nm; all P<0.05). Performance decrements persisted when handgrip strength was adjusted for lean body mass and fat mass explaining 66% of the variance; peak power adjusted for age, lean body mass, fat mass, and height explaining 91% of the variance; and the highest MVC torque (10-degree angle) adjusted for left leg length, lean mass-for-height, and fat mass-for-height Z scores explaining 65% of the variance. This suggests additional factors contribute to the attenuated anaerobic performance.

Introduction: Burnout and stress in medical settings have been associated with despondent staff and decreased productivity. Although Program Coordinators (PCs) play an integral role in residency training programs, there exist few, if any, interventions aimed at addressing their burnout., Methods: A longitudinal study design was used to evaluate data from residency/fellowship training PCs who participated in a wellness retreat held at a single institution in August 2016. Subjects completed anonymous, pre- and post-retreat questionnaires in addition to a 3-month follow-up questionnaire, which included questions used to assess aspects of job demand, resiliency, and well-being. The seven-item Physician Well-Being Index and a logistic regression model were used to assess well-being. Mean values and SDs were reported to examine changes in mental health scores and participants' job satisfaction over the course of the intervention., Results: Nineteen of the 45 (43%) invited residency/fellowship training PCs completed data collection. Coordinators ranged in age from 25 to 64 years; all were female. Well-being, sleep, resiliency, and employee satisfaction scores improved over the assessment period. Well-being scores initially decreased by 0.37 at the postassessment, but increased at follow-up (mean: 2.0; SD 1.7). Stress scores increased from baseline to post, but decreased from baseline to follow-up: 0.2 and -0.2, respectively., Discussion: Residency PCs experienced improvements in mental quality of life, resiliency, stress, and sleep scores on attending the wellness program. Attention to such findings may have important implications, as we address the burnout crisis in the medical education community.

Background: Informed by the Pediatric Self-Management Model, the present study tested relationships between parent and family functioning, sickle cell disease (SCD) self-management, and health outcomes for children with SCD., Method: 83 children with SCD and a parent completed baseline data as part of a larger investigation of a family-based, problem-solving intervention for children with SCD (M age = 8.47). Youth and parents completed a measure of child health-related quality of life (HRQOL), and parents completed measures of family efficacy, parenting stress, and SCD self-management. SCD pain episodes and urgent health utilization information over the past year were obtained via medical chart review., Results: SCD self-management mediated the relationship between parent-reported family efficacy and parent proxy HRQOL, as well as the relationship between parenting stress and child and parent proxy HRQOL. Mediation models were nonsignificant for outcomes beyond HRQOL, including SCD pain episodes and urgent health utilization., Conclusion: Fostering family efficacy and reducing parenting stress may be meaningful intervention targets for improving SCD self-management and child HRQOL among school-aged children. Although findings were consistent with the Pediatric Self-Management Model in terms of HRQOL, the model was not supported for pain episodes or urgent health utilization, highlighting the need for multi-method, longitudinal research on the SCD self-management behaviors that are linked to preventable health outcomes.

Background and Objective: Recurrent hospital admissions for patients with sickle cell disease (SCD) are costly and contribute to a low quality of life for patients. We implemented a clinical pathway to safely discharge SCD patients with fever who are evaluated in the emergency department (ED) of a large tertiary care center., Methods: An interdisciplinary team of ED and hematology physicians, nurses, and an improvement advisor developed a clinical pathway that identified febrile SCD patients at low risk of serious bacterial infection based on historical, clinical, and laboratory criteria who could be discharged from the ED. Phone follow-up was planned through the use of an automated electronic notification that was sent to an established hematology follow-up pool at the time of ED discharge. We conducted two "fake front end" trials in the ED to receive feedback on our process before full implementation. A postpathway implementation quality improvement team monitored discharge rates, phone follow-up rates and adverse events., Results: In the first 9 weeks postpathway implementation, 100 SCD patients were evaluated for fever; 84 (24%) met low-risk criteria and were discharged home. This reduction in admission rate has been maintained throughout the 3 years postimplementation. Successful phone follow-up was achieved in all discharged patients within 24 hours and no adverse events were identified., Conclusions: Low-risk febrile patients with SCD can be safely discharged from the ED. An automated notification system within the electronic medical record system can facilitate patient follow-up after ED discharge. Future quality improvement efforts aimed to further reduce admissions in this population should target patients with modifiable risk factors for serious bacterial infection.

Newborn screening (NBS) identifies infants with rare conditions to prevent death or the onset of irreversible morbidities. Conditions on the Health and Human Services Secretary's Recommended Uniform Screening Panel have been adopted by most state NBS programs, providing a consistent approach for identification of affected newborns across the United States. Screen-positive newborns are identified and referred for confirmatory diagnosis and follow-up. The designation of a clinically significant phenotype precursor to a clinical diagnosis may vary between clinical specialists, resulting in diagnostic variation. Determination of disease burden and birth prevalence of the screened conditions by public health tracking is made challenging by these variations. This report describes the development of a core group of new case definitions, along with implications, plans for their use, and links to the definitions that were developed by panels of clinical experts. These definitions have been developed through an iterative process and are piloted in NBS programs. Consensus public health surveillance case definitions for newborn screened disorders will allow for consistent categorization and tracking of short- and long-term follow-up of identified newborns at the local, regional, and national levels., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

Approximately 100,000 Americans have sickle cell disease (SCD), a group of recessively inherited red blood cell disorders characterized by abnormal hemoglobin, called hemoglobin S or sickle hemoglobin, in the red blood cells. Persons with hemoglobin SS or hemoglobin Sß 0 thalassemia, also known as sickle cell anemia (SCA), have the most severe form of SCD. Hemoglobin SC disease and hemoglobin Sß + thalassemia are other common forms of SCD. Red blood cells that contain sickle hemoglobin are inflexible and can stick to vessel walls, causing a blockage that slows or stops blood flow. When this happens, oxygen cannot reach nearby tissues, leading to attacks of sudden, severe pain, called pain crises, which are the clinical hallmark of SCD. The red cell sickling and poor oxygen delivery can also cause damage to the brain, spleen, eyes, lungs, liver, and multiple other organs and organ systems. These chronic complications can lead to increased morbidity, early mortality, or both. Tremendous strides in treating and preventing the complications of SCD have extended life expectancy. Now, nearly 95% of persons born with SCD in the United States reach age 18 years (1); however, adults with the most severe forms of SCD have a life span that is 20-30 years shorter than that of persons without SCD (2).

Background: In utero hematopoietic cell transplantation (IUHCT) has curative potential for sickle cell disease (SCD) but carries a risk of fetal demise., Methods: We assessed the conditions under which parents of children with SCD and young adults with SCD would consider IUHCT in a future pregnancy, given a 5% fixed risk of fetal demise. Participants were randomized to consider a hypothetical cure rate (20%, 40%, or 70%). Subsequently, cure rate was either increased or decreased depending on the previous answer to reveal the lowest acceptable rate. Participants also completed the Pediatric Research Participation Questionnaire (PRPQ) and an omission scale., Results: Overall, 74 of 79 (94%) participants were willing to consider IUHCT, and 52 (66%) participants accepted IUHCT at a cure rate of 40%, the estimated rate of therapeutic mixed chimerism. Participants with higher scores on the PRPQ perceived benefits scale were more likely to participate at lower cure rates (OR 1.08, p=0.007) and participants with a greater degree of omission bias were less likely to participate at lower cure rates (OR 0.83, p=0.04). Demographics and SCD severity were not significantly associated with acceptability of IUHCT., Conclusion: This study suggests that the majority of parents >and young adults would consider IUHCT under expected therapeutic conditions.

Background: Detecting change in health status over time and ascertaining meaningful changes are critical elements when using health-related quality of life (HRQL) instruments to measure patient-centered outcomes. The PedsQL™ Sickle Cell Disease module, a disease specific HRQL instrument, has previously been shown to be valid and reliable. Our objectives were to determine the longitudinal validity of the PedsQL™ Sickle Cell Disease module and the change in HRQL that is meaningful to patients., Methods: An ancillary study was conducted utilizing a multi-center prospective trial design. Children ages 4-21 years with sickle cell disease admitted to the hospital for an acute painful vaso-oclusive crisis were eligible. Children completed HRQL assessments at three time points (in the Emergency Department, one week post-discharge, and at return to baseline (One to three months post-discharge). The primary outcome was change in HRQL score. Both distribution (effect size, standard error of measurement (SEM)) and anchor (global change assessment) based methods were used to determine the longitudinal validity and meaningful change in HRQL. Changes in HRQL meaningful to patients were identified by anchoring the change scores to the patient's perception of global improvement in pain., Results: Moderate effect sizes (0.20-0.80) were determined for all domains except the Communication I and Cognitive Fatigue domains. The value of 1 SEM varied from 3.8-14.6 across all domains. Over 50% of patients improved by at least 1 SEM in Total HRQL score. A HRQL change score of 7-10 in the pain domains represented minimal perceived improvement in HRQL and a HRQL change score of 18 or greater represented moderate to large improvement., Conclusions: The PedsQL™ Sickle Cell Disease Module is responsive to changes in HRQL in patients experiencing acute painful vaso-occlusive crises. The study data establish longitudinal validity and meaningful change parameters for the PedsQL™ Sickle Cell Disease Module., Trial Registration: ClinicalTrials.gov (study identifier: NCT01197417 ). Date of registration: 08/30/2010.

Objectives: The purpose of this study was to describe the clinical phenotype of widespread pain (WSP) among youth with sickle cell disease (SCD) hospitalized with vasoocclusive pain., Materials and Methods: One hundred fifty-six youth with SCD, between 7 and 21 years of age hospitalized at 4 children's hospitals for a vasoocclusive episode were evaluated. Data were collected during 1 day of the hospitalization., Results: Using the 2010 American College of Rheumatology guidelines, 21.8% of patients were identified as having WSP (pain in 7 or more unique body locations). Patients classified as having WSP had higher pain intensity (6.5 vs. 5.6; t=2.19, P=0.03) higher pain burden (13.0 vs. 9.8; t=3.09, P=0.002), higher acute functional disability (22.1 vs. 16.5; t=2.43, P=0.016), higher chronic functional disability (30.4 vs. 22.2; t=2.31, P=0.02), lower positive affect (22.9 vs. 27.6; t=2.23, P=0.027), and lower quality of life (56.2 vs. 62.9; t=1.99, P=0.049) than those youth with SCD without WSP., Discussion: Assessment of WSP may identify a unique clinical phenotype of youth with SCD with differing treatment needs.