Measurement properties of Patient Reported Outcomes Measurement Information System domains for children with type 1 diabetes.

OBJECTIVE: Patient Reported Outcomes Measurement Information System (PROMIS) includes numerous domains to assess functioning among the pediatric population. These domains, however, have not been evaluated for use in children with type 1 diabetes (T1D). The objective of this study was to determine the measurement properties of PROMIS domains (pain behavior, pain quality, physical stress experience, physical activity, strength impact, and profile-25) in children with T1D. METHODS: This is a cross-sectional study of children with T1Drecruited from tertiary care facilities. To determine construct validity, we compared PROMIS T-scores between known-groups based on (a) glycemic control, hemoglobin A1c (HbA1c%) and (b) self-reported general health, using t test or analysis of variance. Reliability was determined using Cronbach's alpha and item response theory reliability. We also determined agreement between parent-proxy and child self-report PROMIS scores. RESULTS: Our study included 192 children, mean age 12.7 (SD = 2.9) years, eligible to self-report PROMIS surveys. There were significant differences in physical stress experience and pain intensity between children with HbA1c < 10% and those with HbA1c ≥ 10%. There also were significant differences in T-scores for all domains except physical function mobility and strength impact among children with poor/fair, good, very good/excellent general health. All valid domains had reliability >0.70. More than 40% of child-parent pairs were in agreement, with intraclass correlations coefficients (ICC) ranging between 0.41 and 0.63 for all domains, except pain behavior (%agreement = 23%; ICC = 0.29). CONCLUSIONS: Most of the PROMIS domains tested are valid, reliable, and able to differentiate children with T1D who report different general health states. There is moderate agreement between child-parent pairs for all domains except pain behavior.

Neuropathic pain is associated with poor health-related quality of life in adolescents with sickle cell disease: A preliminary report.

BACKGROUND: Neuropathic pain is associated with poor health-related quality of life (HRQL) in pain conditions other than sickle cell disease (SCD); this relationship in SCD is unknown. We investigated this relationship and hypothesized neuropathic pain is associated with poor HRQL in adolescents with SCD. METHODS: We conducted a cross-sectional study of patients with SCD ages 13-18 years during baseline health. Primary outcome was HRQL, assessed by the PedsQL SCD Module (child self-report, parent proxy report). PedsQL is scored from 0 to 100, with higher scores indicating better HRQL. Neuropathic pain was assessed using the painDETECT questionnaire (scored 0-38); higher scores indicated greater likelihood of neuropathic pain. All completed both PedsQL SCD Module and painDETECT questionnaire. Descriptive statistics were used and associations between painDETECT and PedsQL Total Score, Pain Impact, Pain and Hurt, and Pain Management and Control Scores were determined via Pearson correlation. Significance was P < .05. RESULTS: Twelve patients were enrolled. Median (interquartile range [IQR]) age was 15 (14-16.5) years, 75% were female, and 83% were on hydroxyurea. Higher painDETECT scores were significantly associated with lower PedsQL SCD Module child self-report Pain and Hurt Scores (r = -0.68, P = .01). Higher painDETECT scores were also significantly associated with lower PedsQL parent proxy-report Total Scores (r = -0.64, P = .03) and Pain and Hurt Scores (r = -0.67, P = .02). CONCLUSIONS: These data suggest that adolescents with SCD and neuropathic pain have poor HRQL even in their baseline state of health. Prospective, larger studies are needed to confirm this preliminary finding and explore a multimodal approach for pain assessment in SCD.

Characterization of a mouse model of sickle cell trait: parallels to human trait and a novel finding of cutaneous sensitization.

Sickle cell trait (SCT) has classically been categorized as a benign condition except in rare cases or upon exposure to severe physical conditions. However, several lines of evidence indicate that individuals with SCT are not always asymptomatic, and additional physiological changes and risks may remain unexplored. Here, we utilized mice harbouring one copy of normal human ß globin and one copy of sickle human ß globin as a model of SCT to assess haematological, histopathological and somatosensory outcomes. We observed that SCT mice displayed renal and hepatic vascular congestion after exposure to hypoxia. Further, we observed that SCT mice displayed increased cold aversion as well as mechanical and heat sensitivity, though to a lesser degree than homozygous sickle cell disease mice. Notably, mechanical hypersensitivity increased following hypoxia and reoxygenation. Overall our findings suggest that SCT is not entirely benign, and further assessment of pain and cutaneous sensitization is warranted both in animal models and in clinical populations.

A novel hemoglobin-binding peptide reduces cell-free hemoglobin in murine hemolytic anemia.

Hemolysis can saturate the hemoglobin (Hb)/heme scavenging system, resulting in increased circulating cell-free Hb (CF-Hb) in hereditary and acquired hemolytic disease. While recent studies have suggested a central role for intravascular hemolysis and CF-Hb in the development of vascular dysfunction, this concept has stimulated considerable debate. This highlights the importance of determining the contribution of CF-Hb to vascular complications associated with hemolysis. Therefore, a novel Hb-binding peptide was synthesized and linked to a small fragment of apolipoprotein E (amino acids 141-150) to facilitate endocytic clearance. Plasma clearance of hE-Hb-b10 displayed a rapid phase t(1/2) of 16 min and slow phase t(1/2) of 10 h, trafficking primarily through the liver. Peptide hE-Hb-B10 decreased CF-Hb in mice treated with phenylhydrazine, a model of acute hemolysis. Administration of hE-Hb-B10 also attenuated CF-Hb in two models of chronic hemolysis: Berkeley sickle cell disease (SS) mice and mice with severe hereditary spherocytosis (HS). The hemolytic rate was unaltered in either chronic hemolysis model, supporting the conclusion that hE-Hb-B10 promotes CF-Hb clearance without affecting erythrocyte lysis. Interestingly, hE-Hb-B10 also decreased plasma ALT activity in SS and HS mice. Although acetylcholine-mediated facialis artery vasodilation was not improved by hE-Hb-B10 treatment, the peptide shifted vascular response in favor of NO-dependent vasodilation in SS mice. Taken together, these data demonstrate that hE-Hb-B10 decreases CF-Hb with a concomitant reduction in liver injury and changes in vascular response. Therefore, hE-Hb-B10 can be used to investigate the different roles of CF-Hb in hemolytic pathology and may have therapeutic benefit in the treatment of CF-Hb-mediated tissue damage.

Transient receptor potential vanilloid 1 mediates pain in mice with severe sickle cell disease.

Pain is the leading cause of emergency department visits, hospitalizations, and daily suffering in individuals with sickle cell disease (SCD). The pathologic mechanisms leading to the perception of pain during acute RBC sickling episodes and development of chronic pain remain poorly understood and ineffectively treated. We provide the first study that explores nociceptor sensitization mechanisms that contribute to pain behavior in mice with severe SCD. Sickle mice exhibit robust behavioral hypersensitivity to mechanical, cold, and heat stimuli. Mechanical hypersensitivity is further exacerbated when hypoxia is used to induce acute sickling. Behavioral mechanical hypersensitivity is mediated in part by enhanced excitability to mechanical stimuli at both primary afferent peripheral terminal and sensory membrane levels. In the present study, inhibition of the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) with the selective antagonist A-425619 reversed the mechanical sensitization at both primary afferent terminals and isolated somata, and markedly attenuated mechanical behavioral hypersensitivity. In contrast, inhibition of TRPA1 with HC-030031 had no effect on mechanical sensitivity. These results suggest that the TRPV1 receptor contributes to primary afferent mechanical sensitization and a substantial portion of behavioral mechanical hypersensitivity in SCD mice. Therefore, TRPV1-targeted compounds that lack thermoregulatory side effects may provide relief from pain in patients with SCD.

Surveillance for the Rare Condition of Sickle Cell Disease in Wisconsin.

INTRODUCTION: Despite universal newborn screening, there is no comprehensive surveillance system to understand the sickle cell disease population in Wisconsin. METHODS: We initiated the development of a sickle cell disease surveillance system by linking newborn screening data and electronic health records from 2 large tertiary health care institutions in Wisconsin: Children's Wisconsin and Froedtert Hospital. RESULTS: There were 1478 individuals within the 3 data sources. One hundred thirty-two (82%) of 159 identified by newborn screening from 2013 through 2019 received care at Children's Wisconsin. The majority of individuals with sickle cell disease at Children's Wisconsin and Froedtert Hospital resided in Milwaukee County. DISCUSSION: The new surveillance program will increase our understanding of the sickle cell disease population in Wisconsin and help improve quality of care and health outcomes.