Addressing Recruitment Challenges in the Engage-HU Trial in Young Children with Sickle Cell Disease

Background: Sickle cell disease (SCD) is a genetic disorder that causes significant medical and neurologic morbidity in children. Hydroxyurea (HU) is the primary medication used to prevent these complications. National Heart, Lung, and Blood Institute (NHLBI) guidelines recommend offering HU to children as young as 9 months of age with SCD (HbSS or HbSB0 thalassemia) using a shared decision-making approach. Although HU has proven efficacious it remains underutilized and caregivers report that they are not always actively involved in the decision to initiate this therapy. Reasons for limited HU uptake likely include lack of clinician knowledge and training and negative caregiver perceptions. Thus, we developed the Engage-HU trial as a novel approach to address HU utilization barriers. A critical consideration for this trial was that SCD primarily affects individuals of African and Hispanic/Latino descent. In these minority populations, intervention trials are sometimes terminated early because of recruitment difficulties related to mistrust of research, caregiver burden, and transportation issues. As such, the Engage-HU trial design included best-practice strategies for recruiting people of color in research. This study describes these strategies, the initial recruitment plan, preliminary recruitment outcomes and strategies, and our procedural adaptations. Study Design and Methods: Engage-HU is a randomized control trial (NCT03442114) to assess how clinicians can engage caregivers in a shared discussion that considers their values and preferences and includes evidence that supports HU. Engage-HU compares two dissemination methods for clinicians to facilitate shared decision-making with caregivers of young children with SCD: 1) the American Society of Hematology Pocket Guide, and 2) the HU Shared-Decision Making (H-SDM) Toolkit. The study aims to recruit 174 caregivers and evaluate the effectiveness of the dissemination methods on patient-centered outcomes (caregiver confidence in decision-making and perceptions of experiencing shared decision-making) as well as HU uptake and child health outcomes. Eligible children are aged 0 to 5 years, candidates for HU, and their caregiver has not made a decision about HU in the past 3 months. The trial is being conducted at 9 sites in the United States and uses a stepped-wedge design. Data will be analyzed based on the intent-to-treat principle. All participants will remain in the arm of the study to which they were randomized, regardless of whether or not they receive the assigned dissemination method. The primary endpoints are caregiver decisional uncertainty and caregiver perception of shared decision-making measured using validated tools. Data will be analyzed using a linear mixed effects regression model with a robust variance estimator and maximum likelihood estimation with observations clustered within site. The Engage-HU trial includes adaptations to increase recruitment such as tailored messaging, a relational recruitment approach, streamlined data collection, and a Stakeholder Advisory Committee. However, even with these adaptations, the first 6-months of the trial yielded lower than anticipated recruitment. Rather than terminate the trial or accept low enrollment, the research team implemented a series of recruitment strategies to address barriers including helping to improve research coordinator knowledge of the study purpose and adjusting no-show and follow-up procedures (e.g., calls to families after missed appointments and reminder calls before appointments). Site clinicians and clinic staff were provided with additional training so they could give more context about Engage-HU to caregivers and the study principal investigator led monthly "all coordinator" calls to provide support by sharing updates and experiences about successful recruitment. Implementation of these strategies resulted in triple the number of enrollments over the next 7-months compared to the previous 6-months (Table 1). Our goal in sharing this information is to provide lessons learned that can be implemented in future trials with the systematically underserved SCD population. It is also anticipated that methods described here may also inform clinical approaches to better engage caregivers of young children around critical clinical conversations, such as initiating medications like HU. Disclosures King: Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioline: Consultancy; RiverVest: Consultancy; Novimmune: Research Funding; Celgene: Consultancy; Tioma Therapuetics: Consultancy; Amphivena Therapeutics: Research Funding; WUGEN: Current equity holder in private company; Cell Works: Consultancy; Incyte: Consultancy. Smith-Whitley:Prime: Other: Education material; Celgene: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Neumayr:Emmaus: Consultancy; Bayer: Consultancy; CTD Holdings: Consultancy; Pfizer: Consultancy; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Micelle: Other: Site principal investigator; GBT: Other: Site principal investigator; PCORI: Other: site principal investigator; Novartis: Other: co-investigator; Bluebird Bio: Other: co-investigator; Sangamo Therapeutics: Other; Silarus: Other; Celgene: Other; La Jolla Pharmaceuticals: Other; Forma: Other; Imara: Other; National Heart, Lung, and Blood Institute: Other; Health Resources and Services Administration: Other; Centers for Disease Control and Prevention: Other; Seattle Children's Research: Other. Yates:Novartis: Research Funding. Thompson:Novartis: Consultancy, Honoraria, Research Funding; CRISPR/Vertex: Research Funding; BMS: Consultancy, Research Funding; Baxalta: Research Funding; Biomarin: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding. </jats:sec

Engaging Caregivers and Providers of Children With Sickle Cell Anemia in Shared Decision Making for Hydroxyurea: Protocol for a Multicenter Randomized Controlled Trial

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

KG2B, a collaborative benchmarking exercise for estimating the permeability of the Grimsel granodiorite - Part 1: Measurements, pressure dependence and pore-fluid effects

Measuring the permeability of tight rocks remains a challenging task. In addition to the traditional sources of errors that affect more permeable formations (e.g. sample selection, non-representative specimens, disturbance introduced during sample acquisition and preparation), tight rocks can be particularly prone to solid–fluid interactions and thus more sensitive to the methods, procedures and techniques used to measure permeability. To address this problem, it is desirable to collect, for a single material, measurements obtained by different methods and pore-fluids. For that purpose a collaborative benchmarking exercise involving 24 laboratories was organized for measuring the permeability of a single low permeability material, the Grimsel granodiorite, at a common effective confining pressure (5 MPa). The objectives of the benchmark were: (i) to compare the results for a given method, (ii) to compare the results between different methods, (iii) to analyze the accuracy of each method, (iv) to study the influence of experimental conditions (especially the nature of pore fluid), (v) to discuss the relevance of indirect methods and models and finally (vi) to suggest good practice for low permeability measurements. In total 39 measurements were collected that allowed us to discuss the influence of (i) pore-fluid, (ii) measurement method, (iii) sample size and (iv) pressure sensitivity. Discarding some outliers from the bulk data set (4 out of 39) an average permeability of 1.11 × 10−18 m² with a standard deviation of 0.57 × 10−18 m² was obtained. The most striking result was the large difference in permeability for gas measurements compared to liquid measurements. Regardless of the method used, gas permeability was higher than liquid permeability by a factor approximately 2 (kgas = 1.28 × 10−18 m² compared to kliquid = 0.65 × 10−18 m²). Possible explanations are that (i) liquid permeability was underestimated due to fluid-rock interactions (ii) gas permeability was overestimated due to insufficient correction for gas slippage and/or (iii) gases and liquids do not probe exactly the same porous networks. The analysis of Knudsen numbers shows that the gas permeability measurements were performed in conditions for which the Klinkenberg correction is sufficient. Smaller samples had a larger scatter of permeability values, suggesting that their volume were below the Representative Elementary Volume. The pressure dependence of permeability was studied by some of the participating teams in the range 1–30 MPa and could be fitted to an exponential law k = ko.exp(–γPeff) with γ = 0.093 MPa−1. Good practice rules for measuring permeability in tight materials are also provided

Impairments in Episodic-Autobiographical Memory and Emotional and Social Information Processing in CADASIL during Mid-Adulthood

Staniloiu A, Woermann FG, Markowitsch HJ. Impairments in Episodic-Autobiographical Memory and Emotional and Social Information Processing in CADASIL during Mid-Adulthood. Frontiers in Behavioral Neuroscience. 2014;8: 227.Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) – is the most common genetic source of vascular dementia in adults, being caused by a mutation in NOTCH3 gene. Spontaneous de novo mutations may occur, but their frequency is largely unknown. Ischemic strokes and cognitive impairments are the most frequent manifestations, but seizures affect up to 10% of the patients. Herein, we describe a 47-year-old male scholar with a genetically confirmed diagnosis of CADASIL (Arg133Cys mutation in the NOTCH3 gene) and a seemingly negative family history of CADASIL illness, who was investigated with a comprehensive neuropsychological testing battery and neuroimaging methods. The patient demonstrated on one hand severe and accelerated deteriorations in multiple cognitive domains such as concentration, long-term memory (including the episodic-autobiographical memory domain), problem solving, cognitive flexibility and planning, affect recognition, discrimination and matching, and social cognition (theory of mind). Some of these impairments were even captured by abbreviated instruments for investigating suspicion of dementia. On the other hand the patient still possessed high crystallized (verbal) intelligence and a capacity to put forth a façade of well-preserved intellectual functioning. Although no definite conclusions can be drawn from a single case study, our findings point to the presence of additional cognitive changes in CADASIL in middle adulthood, in particular to impairments in the episodic-autobiographical memory domain and social information processing (e.g., social cognition). Whether these identified impairments are related to the patient’s specific phenotype or to an ascertainment bias (e.g., a paucity of studies investigating these cognitive functions) requires elucidation by larger scale research

Toward a Mathematical Holographic Principle

In work started in [17] and continued in this paper our objective is to study selectors of multivalued functions which have interesting dynamical properties, such as possessing absolutely continuous invariant measures. We specify the graph of a multivalued function by means of lower and upper boundary maps $\tau_{1}$ and $\tau_{2}.$ On these boundary maps we define a position dependent random map $R_{p}=\{\tau_{1},\tau_{2};p,1-p\},$ which, at each time step, moves the point $x$ to $\tau_{1}(x)$ with probability $p(x)$ and to $\tau_{2}(x)$ with probability $1-p(x)$. Under general conditions, for each choice of $p$, $R_{p}$ possesses an absolutely continuous invariant measure with invariant density $f_{p}.$ Let $\boldsymbol\tau$ be a selector which has invariant density function $f.$ One of our objectives is to study conditions under which $p(x)$ exists such that $R_{p}$ has $f$ as its invariant density function. When this is the case, the long term statistical dynamical behavior of a selector can be represented by the long term statistical behavior of a random map on the boundaries of $G.$ We refer to such a result as a mathematical holographic principle. We present examples and study the relationship between the invariant densities attainable by classes of selectors and the random maps based on the boundaries and show that, under certain conditions, the extreme points of the invariant densities for selectors are achieved by bang-bang random maps, that is, random maps for which $p(x)\in \{0,1\}.