Birth Prevalence of Sickle Cell Disease and County-Level Social Vulnerability - Sickle Cell Data Collection Program, 11 States, 2016-2020.

Sickle cell disease (SCD) remains a public health priority in the United States because of its association with complex health needs, reduced life expectancy, lifelong disabilities, and high cost of care. A cross-sectional analysis was conducted to calculate the crude and race-specific birth prevalence for SCD using state newborn screening program records during 2016-2020 from 11 Sickle Cell Data Collection program states. The percentage distribution of birth mother residence within Social Vulnerability Index quartiles was derived. Among 3,305 newborns with confirmed SCD (including 57% with homozygous hemoglobin S or sickle ß-null thalassemia across 11 states, 90% of whom were Black or African American [Black], and 4% of whom were Hispanic or Latino), the crude SCD birth prevalence was 4.83 per 10,000 (one in every 2,070) live births and 28.54 per 10,000 (one in every 350) non-Hispanic Black newborns. Approximately two thirds (67%) of mothers of newborns with SCD lived in counties with high or very high levels of social vulnerability; most mothers lived in counties with high or very high levels of vulnerability for racial and ethnic minority status (89%) and housing type and transportation (64%) themes. These findings can guide public health, health care systems, and community program planning and implementation that address social determinants of health for infants with SCD. Implementation of tailored interventions, including increasing access to transportation, improving housing, and advancing equity in high vulnerability areas, could facilitate care and improve health outcomes for children with SCD.

Increasing Visibility of Sickle Cell Disease in Indiana: Establishing Baseline Prevalence Using Integrated Data From Multiple Sources.

OBJECTIVE: The Indiana Sickle Cell Data Collection (IN-SCDC) program aims to provide timely, reliable, and locally relevant information on the sickle cell disease (SCD) population in Indiana to inform public health interventions, research, and policy development. We describe the development of the IN-SCDC program and report the prevalence and geographic distribution of people with SCD in Indiana using an integrated data collection approach. METHODS: Using multiple integrated data sources and case definitions established by the Centers for Disease Control and Prevention, we classified cases of SCD in Indiana during 2015-2019. We calculated the prevalence and incidence of SCD and described characteristics of people with SCD. RESULTS: We identified 1695 people living with SCD in Indiana during the study period. The median age of people living with SCD was 21 years, and 1474 (87.0%) were Black or African American. Most (n = 1596, 91%) resided in metropolitan counties. The age-adjusted prevalence of SCD was 24.7 cases per 100 000 people. The prevalence of SCD among Black or African American people was 209.3 per 100 000 people. The incidence was 1 in 2608 live births overall and 1 in 446 live births among Black or African American people. Eighty-six deaths were confirmed in this population during 2015-2019. CONCLUSIONS: Our results establish a baseline for the IN-SCDC program. Baseline and future surveillance program efforts will help accurately inform standards of care for treatments, identify gaps in coverage and access to care, and provide guidance for legislators and community-based organizations.

Psychometrics and applications of a novel self-report measure of emicizumab adherence: VERITASNexGen.

INTRODUCTION: Treatment adherence is critical to minimize bleeding episodes in persons with haemophilia. Suboptimal adherence increases risk of adverse medical outcomes and negatively impacts quality of life. Assessment of treatment adherence is therefore an integral component of intervention to mitigate the adverse impacts of haemophilia. AIM: To develop and validate a multifactorial, patient (self or caregiver) report adherence measure for emicizumab treatment and report the first patient-report data on adherence to specific components of emicizumab treatment (dosing, timing, injection, planning and bleeds). METHODS: An IRB approved multi-site prospective study enrolled 83 participants with factor VIII deficiency being treated with emicizumab. Participants completed the 25-item VERITAS NexGen (self-report from 50 adults age 18+ years; caregiver-report from 33 parents of children aged 6 months to 17 years) as well as a global adherence rating (GAR) scale. Providers of participants also completed a GAR scale. RESULTS: Most VERITAS-NexGen subscales had good-to-excellent internal consistency reliability, test-retest reliability, and validity. VERITASNexGen scores revealed globally strong patient-reported adherence; however timing and bleed management were reported as greater challenges to adherence compared to dosing and injections. Adults struggled more with timing and planning of injections than caregivers. CONCLUSION: The VERITASNexGen is the first validated multifactorial patient-report measure of adherence designed specifically for emicizumab treatment. Results suggest excellent adherence, with only 4%-13% of participants reporting suboptimal adherence to different components of the treatment regimen. Used in conjunction with other adherence measures, VERITAS-NexGen meets a crucial need for monitoring and understanding patient adherence to emicizumab in clinical and research settings.

Development and Validation of the Patient/Caregiver Reported Hydroxyurea Evaluation of Adherence for Life (HEAL) Scale.

Introduction: Hydroxyurea reduces the incidence of vaso-occlusive episodes, stroke, and respiratory, cardiac, and renal damage in sickle cell disease by increasing fetal hemoglobin. However, because suboptimal adherence to hydroxyurea limits its effectiveness, understanding patient-specific barriers to hydroxyurea adherence could help improve adherence and health outcomes in patients with sickle cell disease. The aim of this single-site, prospective, IRB-approved study was to validate a 24-item patient- and caregiver-reported hydroxyurea treatment adherence questionnaire, the Hydroxyurea Evaluation of Adherence for Life (HEAL) scale. Methods: A sample of 24 adults with sickle cell disease and 16 caregivers of children with sickle cell disease completed the HEAL scale, and a subset of the original sample provided a second HEAL scale for test-retest reliability. HEAL scale results were validated against global adherence ratings from participants and health-care providers, records of access to pill bottles, and laboratory values for fetal hemoglobin and absolute neutrophil count. Results and Discussion: Results demonstrated excellent internal consistency for the HEAL Total score and eight (3-item) subscale scores (Dose, Remember, Plan, Cost, Understand, Effectiveness, Laboratory, and Pharmacy), as well as strong test-retest reliability for all HEAL scores except the Cost subscale. HEAL Total scores correlated significantly with validity measures, including global adherence ratings and lab values. The HEAL scale offers significant clinical potential for understanding adherence in individual sickle cell disease patients and significant research potential for characterizing adherence in persons with sickle cell disease who are treated with hydroxyurea.

A Feasibility Pilot Study of Online Modules of Hydroxyurea and Sickle Cell Disease Care for Adolescents and Young Adults for Family Medicine Residents.

Family medicine (FP) residency programs are located throughout Indiana, and most adults with sickle cell disease (SCD) in Indiana have access to a primary care clinic administered by a FP program. Allen County ranks third in SCD incidence in Indiana, but has few providers for adolescents, young adults (AYAs) and adults with SCD. Initiation of a novel partnership between Indianapolis-based adult hematologists (130 miles distant), and the FP program in Allen County aimed to educate FP residents about SCD, hydroxyurea, transition, and SCD complications. To determine the feasibility of utilizing online learning modules to educate FP residents about SCD care in AYA and adults, 3 online learning modules (comprehensive care of AYAs with SCD, hydroxyurea, and best practices in AYA transition) were developed and continuing medical education-accredited. Electronic pretest and posttest were distributed to 32 FP residents to test the retention of content through an Institutional Review Board approved protocol. This pilot study demonstrates that it is feasible to utilize online educational modules to educate providers about SCD care.

An outpatient critical care transition clinic model reduces admissions/readmissions in medically complex patients.

OBJECTIVES: Reducing hospital admissions in patients with multiple complex chronic conditions is both a quality indicator and cost-effective to health care systems. This study assesses and compares utilization rates and cost of encounters between patients referred and seen in an outpatient critical care transition clinic (Healthy Transitions Clinic [HTC]) and those referred and not seen. STUDY DESIGN: Retrospective cohorts. METHODS: Patients with complex chronic conditions discharged from a tertiary/quaternary acute care hospital or emergency department (March 1, 2015, to February 29, 2016) were referred to an outpatient critical care transition clinic. Comparative cohorts were those patients who attended this transition clinic and those who did not. Pre- and post-HTC referral visits, with health care utilization evaluations including admissions/readmissions, attention to social determinants of health, and cost assessments, were compared among the cohorts. RESULTS: Insurance coverage differed significantly in its distribution between the groups (χ2 = 22.99; P < .001); therefore, an adjusted relative risk model was used. Inpatient admissions significantly increased, by 31%, in the non-HTC cohort (P = .03); a significant increase in the rate of 30-day readmissions (69%) occurred in the HTC group (P < .001) at 6 months post index admission. Length of stay did not differ pre- and post HTC visit. Although not statistically significant, visits to the HTC reduced median all-cost and HTC cohort cost by more than $1 million. CONCLUSIONS: In patients with complex chronic medical conditions with recent hospital admissions, the HTC model appears to reduce both admissions and encounter costs. Further community/regional studies are needed to better define this observation on a longitudinal basis.

Hematopoietic stem cell transplant referral patterns for children with sickle cell disease vary among pediatric hematologist/oncologists' practice focus: A Sickle Cell Transplant Advocacy and Research Alliance (STAR) study.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) provides a curative therapy for children severely affected by sickle cell disease (SCD). Rejection-free survival after matched sibling donor (MSD) HSCT is very high, but adoption of HSCT as a curative SCD therapy has been slow. In this study, we assess providers' perceptions about MSD HSCT for children with variable SCD severity, and determine the influence of provider characteristics on HSCT referrals. PROCEDURE: After our Institutional Review Board deemed the study exempt, American Society of Pediatric Hematology/Oncology Clinical Forum listserv subscribers and American Society of Hematology members who self-identified as pediatric hematologists/oncologists (PHO) were emailed a survey. Analysis was performed to describe and evaluate correlations between participant demographics (including practice focus within PHO) and likelihood of HSCT referral for each scenario. RESULTS: Spearman's rank correlation analysis did not reveal any significant relationship between demographic characteristics except practice focus and likelihood to refer to HSCT for any scenarios. Providers focused on SCD and HSCT were more likely to refer a child who had never been admitted to the hospital or had suboptimal adherence to hydroxyurea than general PHOs. A significantly higher proportion of all respondents would refer a child with ß-thalassemia major (87%) than an asymptomatic child with HbSS (47%, P < .00001) or non-HbSS variant (23%, P < .00001). CONCLUSION: PSCD and HSCT physicians are more likely to refer for MSD HSCT in almost every condition than general PHO practitioners, likely because of increased awareness of long-term effects of SCD and safety of MSD HSCT for children with SCD.

An international registry of patients with plasminogen deficiency (HISTORY).

Plasminogen deficiency is an ultra-rare multisystem disorder characterized by the development of fibrin-rich pseudomembranes on mucous membranes. Ligneous conjunctivitis, which can result in vision impairment or loss, is the most frequent symptom reported. Affected systems may also include the respiratory tract, oropharynx, female reproductive tract, gingiva, middle ear, renal collecting system, skin and central nervous system. Untreated, plasminogen deficiency may result in significant reduction in quality of life and morbidity with potential life-threatening complications. Non-specific therapies are inadequate and plasminogen concentrates are not commercially available. The current understanding of plasminogen deficiency and management of disease symptoms and its progression are based on case reports/series and two small clinical trials. To date there has never been a comprehensive, international study to examine the natural history or optimal therapeutic intervention; knowledge gaps include identification of contributing factors and triggers of disease manifestations, inability to predict disease course, and insufficient real-world data for use of therapeutics. We have created an international, observational study (HISTORY) in a large cohort of persons with plasminogen deficiency and first-degree family members to address these gaps and to advance knowledge and care. HISTORY will build upon the established relationship between the Indiana Hemophilia and Thrombosis Center and the Fondazione Angelo Bianchi Bonomi, IRCCS Ca' Granda Ospedale Maggiore Policlinico - University of Milan and will utilize a modified version of the Prospective Rare Bleeding Disorders Database (PRO-RBDD). A biorepository containing samples from subjects with plasminogen deficiency will be established. This article describes the rationale behind the study and efforts towards its goals.

Adherence to Quality of Care Indicators and Location of Sickle Cell Care Within Indiana.

Newborn screening (NBS) follow-up programs for infants with sickle cell disease (SCD) are highly variable among states. Initiated in 2009, Sickle SAFE, the NBS follow-up program for infants with SCD in Indiana, follows infants through home visits and phone contact. The current study assessed the attainment rates for recently published quality indicators of pediatric SCD care for Sickle SAFE participants. Using retrospective data, we determined the proportion of children who received transcranial Doppler (TCD) screening, influenza, and pneumococcal vaccination and were prescribed hydroxyurea. We calculated the mean age at confirmatory testing, time to receipt of penicillin prophylaxis, and mean age when genetic counseling was offered. One hundred ninety-eight children born with SCD in Indiana between July 1, 2009 and June 30, 2017 were followed for at least 1 year. While 97.5% received at least one dose of conjugated pneumococcal vaccine, vaccination with the 23 valent pneumococcal vaccine varied by location (county) of care (Allen: 14.3%, Lake: 26.7%, St. Joseph: 40.0%, Marion: 73.3%). Overall TCD screening rate for eligible children was 53%; TCD screening rate varied widely by location of care (Lake: 25% vs. Marion: 63.8%). Similarly, hydroxyurea prescribing practices varied significantly by location of care (p < 0.001). Identified gaps in adherence to quality indicators in SCD care will serve as the basis for future quality improvement initiatives.

Population-based surveillance of haemophilia and patient outcomes in Indiana using multiple data sources.

INTRODUCTION: Epidemiological surveillance of haemophilia through linkage of medical records within a US state has not been conducted in 20 years. AIM: The Indiana Haemophilia Surveillance Project aims to identify all persons with haemophilia who resided in Indiana in 2011-2013 and to determine the percentage of patients in Indiana cared for at a federally recognized haemophilia treatment centre (HTC). METHODS: A retrospective review of medical charts was conducted to identify haemophilia cases during the surveillance years. Case-finding methods involved a variety of medical care resources including hospitals, administrative claims data and haematology/oncology clinic reports. RESULTS: In Indiana, 704 unique haemophilia cases were identified. Of those cases, 456 (64.8%) had factor VIII and 248 (35.2%) had factor IX deficiency. Among those with known severity levels (n = 685), 233 (34%) were severe, 185 (27%) were moderate, and 267 (39%) were mild. Overall, 81.7% of the haemophilia patients identified visited an HTC at least once during the three-year study period, which was the requirement for being considered an HTC patient. Age-adjusted prevalence for 2013 was 19.4 haemophilia cases per 100 000 males, 12.7 per 100 000 for factor VIII and 6.7 per 100 000 for factor IX. Incidence of haemophilia over the 10 years prior to the surveillance years was 1:3688 live male births in Indiana. During the surveillance years, 24 cases (3.4%) died. CONCLUSION: We observed higher incidence and prevalence of haemophilia in Indiana compared to previous national estimates, as well as higher HTC utilization among persons with haemophilia.

Return-to-Learn Accommodations and Concussion Perceptions Among Indiana High School Principals.

OBJECTIVE: Care after concussion is important for all patients, although especially critical in children and adolescents because of continued rapid brain growth and maturation. Postconcussion symptoms often lead to impaired school performance. Conflicting data regarding best return-to-learn practices make it difficult for school administrators to develop policies to best accommodate concussed students. We sought to assess high school principals' knowledge of concussion, the personnel responsible for implementing accommodations, and the overall willingness to enact recommended academic accommodations. METHODS: In our cross-sectional study, we surveyed 410 Indiana high school principals (157 responded). Assistant principals were excluded. RESULTS: One-third of the respondents received academic accommodations training for concussed students and more than 80% were somewhat or very comfortable with academic management. Greater than 90% were willing to provide accommodations as long as necessary. However, nearly 40% of responding principals were unlikely or unwilling to implement accommodations for standardized testing. National and state data suggest the median Indiana high school should expect 30 and more concussions per year; more than 90% of principals estimated that fewer than 30 concussions occurred each year at their school. CONCLUSIONS: The underestimation of concussion frequency highlights an opportunity for further education of high school principals to ensure all concussed students receive appropriate return-to-learn accommodations.

Extracellular matrix elasticity and topography: material-based cues that affect cell function via conserved mechanisms.

Chemical, mechanical, and topographic extracellular matrix (ECM) cues have been extensively studied for their influence on cell behavior. These ECM cues alter cell adhesion, cell shape, and cell migration and activate signal transduction pathways to influence gene expression, proliferation, and differentiation. ECM elasticity and topography, in particular, have emerged as material properties of intense focus based on strong evidence these physical cues can partially dictate stem cell differentiation. Cells generate forces to pull on their adhesive contacts, and these tractional forces appear to be a common element of cells' responses to both elasticity and topography. This review focuses on recently published work that links ECM topography and mechanics and their influence on differentiation and other cell behaviors. We also highlight signaling pathways typically implicated in mechanotransduction that are (or may be) shared by cells subjected to topographic cues. Finally, we conclude with a brief discussion of the potential implications of these commonalities for cell based therapies and biomaterial design.

Nanotopographic substrates of poly (methyl methacrylate) do not strongly influence the osteogenic phenotype of mesenchymal stem cells in vitro.

The chemical, mechanical, and topographical features of the extracellular matrix (ECM) have all been documented to influence cell adhesion, gene expression, migration, proliferation, and differentiation. Topography plays a key role in the architecture and functionality of various tissues in vivo, thus raising the possibility that topographic cues can be instructive when incorporated into biomaterials for regenerative applications. In the literature, there are discrepancies regarding the potential roles of nanotopography to enhance the osteogenic phenotype of mesenchymal stem cells (MSC). In this study, we used thin film substrates of poly(methyl methacrylate) (PMMA) with nanoscale gratings to investigate the influence of nanotopography on the osteogenic phenotype of MSCs, focusing in particular on their ability to produce mineral similar to native bone. Topography influenced focal adhesion size and MSC alignment, and enhanced MSC proliferation after 14 days of culture. However, the osteogenic phenotype was minimally influenced by surface topography. Specifically, alkaline phosphatase (ALP) expression was not increased on nanotopographic films, nor was calcium deposition improved after 21 days in culture. Ca: P ratios were similar to native mouse bone on films with gratings of 415 nm width and 200 nm depth (G415) and 303 nm width and 190 nm depth (G303). Notably, all surfaces had Ca∶P ratios significantly lower than G415 films. Collectively, these data suggest that, PMMA films with nanogratings are poor drivers of an osteogenic phenotype.

A safe and efficient method to retrieve mesenchymal stem cells from three-dimensional fibrin gels.

Mesenchymal stem cells (MSCs) display multipotent characteristics that make them ideal for potential therapeutic applications. MSCs are typically cultured as monolayers on tissue culture plastic, but there is increasing evidence suggesting that they may lose their multipotency over time in vitro and eventually cease to retain any resemblance to in vivo resident MSCs. Three-dimensional (3D) culture systems that more closely recapitulate the physiological environment of MSCs and other cell types are increasingly explored for their capacity to support and maintain the cell phenotypes. In much of our own work, we have utilized fibrin, a natural protein-based material that serves as the provisional extracellular matrix during wound healing. Fibrin has proven to be useful in numerous tissue engineering applications and has been used clinically as a hemostatic material. Its rapid self-assembly driven by thrombin-mediated alteration of fibrinogen makes fibrin an attractive 3D substrate, in which cells can adhere, spread, proliferate, and undergo complex morphogenetic programs. However, there is a significant need for simple cost-effective methods to safely retrieve cells encapsulated within fibrin hydrogels to perform additional analyses or use the cells for therapy. Here, we present a safe and efficient protocol for the isolation of MSCs from 3D fibrin gels. The key ingredient of our successful extraction method is nattokinase, a serine protease of the subtilisin family that has a strong fibrinolytic activity. Our data show that MSCs recovered from 3D fibrin gels using nattokinase are not only viable but also retain their proliferative and multilineage potentials. Demonstrated for MSCs, this method can be readily adapted to retrieve any other cell type from 3D fibrin gel constructs for various applications, including expansion, bioassays, and in vivo implantation.

Bone marrow stromal cells stimulate an angiogenic program that requires endothelial MT1-MMP.

Bone marrow-derived stromal/stem cells (BMSCs) have recently been characterized as mediators of tissue regeneration after injury. In addition to preventing fibrosis at the wound site, BMSCs elicit an angiogenic response within the fibrin matrix. The mechanistic interactions between BMSCs and invading endothelial cells (ECs) during this process are not fully understood. Using a three-dimensional, fibrin-based angiogenesis model, we sought to investigate the proteolytic mechanisms by which BMSCs promote vessel morphogenesis. We find that BMSC-mediated vessel formation depends on the proteolytic ability of membrane type 1-matrix metalloproteinase (MT1-MMP). Knockdown of the protease results in a small network of vessels with enlarged lumens. Contrastingly, vessel morphogenesis is unaffected by the knockdown of MMP-2 and MMP-9. Furthermore, we find that BMSC-mediated vessel morphogenesis in vivo follows mechanisms similar to what we observe in vitro. Subcutaneous, cellular fibrin implants in C.B-17/SCID mice form aberrant vasculature when MMPs are inhibited with a broad-spectrum chemical inhibitor, and a very minimal amount of vessels when MT1-MMP proteolytic activity is interrupted in ECs. Other studies have debated the necessity of MT1-MMP in the context of vessel invasion in fibrin, but this study clearly demonstrates its requirement in BMSC-mediated angiogenesis.