Patient-reported outcomes in sickle cell disease and association with clinical and psychosocial factors: Report from the sickle cell disease implementation consortium.

Understanding patient experiences, quality of life, and treatment needs in individuals with sickle cell disease (SCD) is essential in promoting health and well-being. We used measures from the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me), Patient Reported Outcomes Measurement Information System (PROMIS), and Quality of Life in Neurological Disorders (NeuroQol) to evaluate pain impact, sleep impact, social functioning, depressive symptoms, tiredness, and cognitive function (collectively, patient reported outcomes [PROs]) and to identify associated demographic and clinical characteristics. Participants (n = 2201) between 18 and 45 years were recruited through the eight Sickle Cell Disease Implementation Consortium (SCDIC) sites. In multivariate models, PROs were significantly associated with one another. Pain impact was associated with age, education, employment, time since last pain attack, hydroxyurea use, opioid use, sleep impact, social functioning, and cognitive function (F = 88.74, P < .0001). Sleep impact was associated with household income, opioid use, pain impact, social functioning, depressive symptoms, and tiredness (F = 101.40, P < .0001). Social functioning was associated with employment, pain attacks in the past year, autoimmune/inflammatory comorbidities, pain impact, sleep impact, depressive symptoms, tiredness, and cognitive function (F = 121.73, P < .0001). Depressive symptoms were associated with sex, sleep impact, social functioning, tiredness, and cognitive function (F = 239.51, P < .0001). Tiredness was associated with sex, education, sleep impact, social functioning, depressive symptoms, and cognitive function (F = 129.13, P < .0001). These findings reflect the baseline PRO assessments among SCDIC registry participants. Further research is needed to better understand these outcomes and new targets for interventions to improve quality of life and function in people with SCD.

A meta-analysis of toxicities related to hydroxycarbamide dosing strategies.

Due to fear of short-term toxicities, there is nonconsensus of hydroxycarbamide dosing strategy (escalated vs fixed-dosing methods), which contributes to its suboptimal use. We performed a meta-analysis to summarize the incidence rates of toxicities associated with both dosing methods. Summarized incidence rates could not be statistically compared between dosing methods due to sparse data. Summarized neutropenia and thrombocytopenia incidence rates were slightly higher when using escalated dosing than with fixed. Summarized reticulocytopenia was comparable. Summarized hepatic and renal toxicities' incidence rates were slightly higher when using fixed doses than with escalated. We recommend diligent and transparent reporting of toxicities.

Height-corrected low bone density associates with severe outcomes in sickle cell disease: SCCRIP cohort study results.

Low bone mineral density (BMD) disproportionately affects people with sickle cell disease (SCD). Growth faltering is common in SCD, but most BMD studies in pediatric SCD cohorts fail to adjust for short stature. We examined low BMD prevalence in 6- to 18-year-olds enrolled in the Sickle Cell Clinical Research and Intervention Program (SCCRIP), an ongoing multicenter life span SCD cohort study initiated in 2014. We calculated areal BMD for chronological age and height-adjusted areal BMD (Ht-aBMD) z scores for the SCCRIP cohort, using reference data from healthy African American children and adolescents enrolled in the Bone Mineral Density in Childhood Study. We defined low BMD as Ht-aBMD z scores less than or equal to -2 and evaluated its associations with demographic and clinical characteristics by using logistic regression analyses. Of the 306 children and adolescents in our study cohort (mean age, 12.5 years; 50% female; 64% HbSS/Sß0-thalassemia genotype; 99% African American), 31% had low areal BMD for chronological age z scores and 18% had low Ht-aBMD z scores. In multivariate analyses, low Ht-aBMD z scores associated with adolescence (odds ratio [OR], 7.7; 95% confidence interval [CI], 1.94-30.20), hip osteonecrosis (OR, 4.0; 95% CI, 1.02-15.63), chronic pain (OR, 10.4; 95% CI, 1.51-71.24), and hemoglobin (OR, 0.74; 95% CI, 0.57-0.96). Despite adjusting for height, nearly 20% of this pediatric SCD cohort still had very low BMD. As the SCCRIP cohort matures, we plan to prospectively evaluate the longitudinal relationship between Ht-aBMD z scores and markers of SCD severity and morbidity.

A Randomized Study of Exercise and Fitness Trackers in Obese Patients After Total Knee Arthroplasty.

Functional limitations persist in obese patients after total knee arthroplasty (TKA). This study assessed the effect of an exercise program (EP) and fitness trackers (FT) in obese patients with TKA. Sixty patients 1 year after orthopedic surgery were recruited and received a 16-week tailored EP; half were randomized to receive an FT. FT had no measurable effect compared with EP alone. EP improved knee range of motion, strength, and quality-of-life scores. This study provides preliminary evidence that a 16-week EP in obese individuals 1 year post TKA is feasible and effective in improving function and quality of life.

Sickle Cell Clinical Research and Intervention Program (SCCRIP): A lifespan cohort study for sickle cell disease progression from the pediatric stage into adulthood.

BACKGROUND: Previous natural history studies have advanced the understanding of sickle cell disease (SCD), but generally have not included sufficient lifespan data or investigation of the role of genetics in clinical outcomes, and have often occurred before the widespread use of disease-modifying therapies, such as hydroxyurea and chronic erythrocyte transfusions. To further advance knowledge of SCD, St. Jude Children's Research Hospital established the Sickle Cell Clinical Research and Intervention Program (SCCRIP), to conduct research in a clinically evaluated cohort of individuals with SCD across their lifetime. PROCEDURES: Initiated in 2014, the SCCRIP study prospectively recruits patients diagnosed with SCD and includes retrospective and longitudinal collection of clinical, neurocognitive, geospatial, psychosocial, and health outcomes data. Biological samples are banked for future genomics and proteomics studies. The organizational structure of SCCRIP is based upon organ/system-specific working groups and is opened to the research community for partnerships. RESULTS: As of August 2017, 1,044 (92.3% of eligible) patients with SCD have enrolled in the study (860 children and 184 adults), with 11,915 person-years of observation. Population demographics included mean age at last visit of 11.3 years (range 0.7-30.1), 49.8% females, 57.7% treated with hydroxyurea, 8.5% treated with monthly transfusions, and 62.9% hemoglobin (Hb) SS or HbSB0 -thalassemia, 25.7% HbSC, 8.4% HbsB+ -Thalassemia, 1.7% HbS/HPFH, and 1.2% other. CONCLUSIONS: The SCCRIP cohort will provide a rich resource for the conduct of high impact multidisciplinary research in SCD.

Behavioral symptoms and psychiatric disorders in child and adolescent long-term survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only.

BACKGROUND: Prevalence of emotional, behavioral, and psychiatric outcomes in child and adolescent survivors of childhood acute lymphoblastic leukemia treated on a chemotherapy-only protocol were not well defined. METHODS: Self- and parent-reported emotional and behavioral symptoms were assessed for 161 survivors of childhood acute lymphoblastic leukemia (51.0% female; mean [SD] age 12.1[2.6] years; 7.5[1.6] years post-diagnosis). Age- and sex-adjusted scores were calculated for standardized measures and compared with 90th percentile of norms. Frequencies of survivor psychiatric disorders from structured diagnostic interviews with parents were compared with the general population. Parent emotional distress and post-traumatic stress symptoms were assessed. Associations between child symptoms/disorders and parent distress were examined with log-binomial models, adjusting for highest parent education. RESULTS: Compared with population expectations (10%), more survivors self-reported symptoms of inattention (27.9; 95% CI, 21.0%-35.7%), hyperactivity/impulsivity (26.0%; CI, 19.2%-33.6%), and oppositional-defiant behavior (20.1%; CI, 14.1%-27.3%). Parents reported survivors with more symptoms of inattention (23.6%; CI, 17.2%-31.0%), higher frequencies of obsessive-compulsive disorder (10.3% vs 2%) and oppositional defiant disorder (16.0% vs 9.5%), but not attention-deficit/hyperactivity disorder (7.1% vs 7.8%) or generalized anxiety disorder (3.2% vs 4.1%), compared with national norms. Parent-report of child anxiety disorders was associated with parent self-reported emotional distress but not survivor self-report of anxiety. CONCLUSION: A significant minority of survivors have long-term psychiatric morbidity, multi-informant assessment is important to understand these symptom profiles and to inform selection of appropriate interventions. Interventions targeting inattention and oppositional behavior in children and emotional distress in parents are warranted in families with survivors who display behavioral problems.

Evolution of neurocognitive function in long-term survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only.

PURPOSE: The purpose of this study was to determine the evolution of neurocognitive problems from therapy completion to long-term follow-up in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only. METHODS: We evaluated whether attention problems observed at therapy completion evolve into long-term executive dysfunction in 158 survivors treated on a single institution protocol. Treatment data (high-dose intravenous methotrexate exposure [serum concentration] and triple intrathecal chemotherapy injections) were collected. Parent report of behavior and direct cognitive testing of survivors was conducted at end of therapy, and survivors completed neurocognitive testing when > 5 years post-diagnosis. RESULTS: At the end of chemotherapy, survivors (52% female; mean age 9.2 years) demonstrated higher frequency of impairment in sustained attention (38%) and parent-reported inattention (20%) compared to population expectations (10%). At long-term follow-up, survivors (mean age 13.7 years; 7.6 years post-diagnosis) demonstrated higher impairment in executive function (flexibility 24%, fluency 21%), sustained attention (15%), and processing speed (15%). Sustained attention improved from end of therapy to long-term follow-up (p < 0.001). Higher methotrexate AUC and greater number of intrathecal injections were associated with attention problems (p = 0.009, p = 0.002, respectively) at the end of chemotherapy and executive function (p < 0.001, p = 0.02, respectively) problems at long-term follow-up. Attention problems at the end of therapy were not associated with executive function problems at long-term follow-up (p's > 0.05). The direct effect of chemotherapy exposure predicted outcomes at both time points. CONCLUSIONS AND IMPLICATIONS FOR CANCER SURVIVORS: Survivors should be monitored for neurocognitive problems well into long-term survivorship, regardless of whether they show attention problems at the end of therapy. Treatment exposures are the best predictor of long-term complications.

Factors associated with residential mobility during pregnancy.

Our objective was to determine the factors associated with residential moving during pregnancy, as it may increase stress during pregnancy and affect birth outcomes. Data were obtained from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study. Participants were recruited from December 2006 to June 2011 and included 1,448 pregnant women. The average gestational age at enrollment was 23 weeks. The primary outcome of residential mobility was defined as any change in address during pregnancy. Multivariate regression was used to assess the adjusted associations of factors with residential mobility. Out of 1,448 participants, approximately 9 percent moved between baseline (enrollment) and delivery. After adjusting for covariates, mothers with lower educational attainment [less than high school (adjusted odds ratio [aOR] = 3.74, 95% confidence interval [CI] = 1.78, 7.85) and high school/technical school (aOR = 3.57, 95% CI = 2.01, 6.32) compared to college degree or higher], and shorter length of residence in neighborhood were more likely to have moved compared to other mothers. Length of residence was protective of mobility (aOR = 0.91, 95% CI = 0.86, 0.96 per year). Increased understanding of residential mobility during pregnancy may help improve the health of mothers and their children.

Active Travel to and From School Among School-Age Children During 1997-2011 and Associated Factors in China.

BACKGROUND: Active travel to school (ATS) is positively associated with various health indicators. The rapid social, economic, and environmental changes in China provide a unique setting to study changes and predictors of ATS over time. METHODS: Using logistic regression modeling, we analyzed data from the China Health and Nutrition Survey during 1997 to 2011 (N = 9487, ages 6 to 17 years) to estimate the change over time in ATS and to identify associated factors. RESULTS: The prevalence of reported ATS among children dropped from 95.8% in 1997 to 69.3% in 2011. ATS was common in children living closer to school, in middle school, from low-income households, with low parental education status, and those without a private vehicle. Children who were living in a metropolitan area and who had more than 40 minutes of total PA per day were less likely to report ATS. CONCLUSIONS: The decrease of ATS had been concurrent with the increase of the children living at a longer distance from school and the increase of household owning private vehicles which were associated with the rapid urbanization and economic growth in China. Factors associated with the decreased ATS in China are similar to other countries but the underlying reasons may be different.

Physical Function and Physical Activity in Obese Adults After Total Knee Arthroplasty.

Obese patients are more likely to have osteoarthritis and total knee arthroplasty (TKA). This investigation sought to evaluate physical function, activity level, and quality of life (QOL). Obese participants near 1-year postsurgical follow-up appointment were recruited. Evaluation included QOL and activity questionnaire, medical histories, anthropometrics, strength, and aerobic capacity. Sixty participants completed assessments. Obese TKA patients have physical performance limitations and low physical activity levels 1 year after surgery and completion of postoperative rehabilitation.

Shoulder Electromyography Measurements During Activities of Daily Living and Routine Rehabilitation Exercises.

Study Design Controlled laboratory study. Background The activity of the rotator cuff muscles has not previously been measured with indwelling electromyography (EMG) comparing ambulation and other movements. Knowledge of the relative contribution of these muscles during various tasks may help to guide rehabilitation progression. Objective To measure activity of the rotator cuff muscles and other shoulder muscles during normal ambulation, shirt and sling donning and doffing, and rehabilitation tasks commonly performed after rotator cuff surgery. Methods In 28 volunteers (15 men, 13 women; mean age, 32.2 years), indwelling EMG activity was measured in the supraspinatus, infraspinatus, teres minor, and subscapularis muscles during various tasks; and surface EMG activity was measured in the middle deltoid, biceps, and upper trapezius muscles. Results Using median EMG activity, in general, donning and doffing a shirt or sling recruited the rotator cuff muscles more than the other 7 tasks tested. Self-ranging motion using pulleys, especially in the scapular plane, was also consistently associated with greater recruitment of the shoulder muscles. Pendulum exercises, passive range of motion by a physical therapist, and self-ranging motion with a dowel recruited the shoulder muscles to a lesser extent. Conclusion Our results demonstrate that rehabilitation tasks such as pendulum exercises, passive range of motion by a physical therapist, and self-ranging motion with a dowel show low EMG activity, whereas pulleys in the sagittal plane and scapular plane show greater activity. Scapular plane activity was consistently higher than sagittal plane activity. Of all the tasks assessed, ambulation without a sling and donning and doffing a sling and a shirt consistently showed the highest activity. J Orthop Sports Phys Ther 2016;46(5):375-383. Epub 6 Apr 2016. doi:10.2519/jospt.2016.6090.

Birth Prevalence of Sickle Cell Trait and Sickle Cell Disease in Shelby County, TN.

BACKGROUND: Accurate quantification of the regional burden of sickle cell disease (SCD) is vital to allocating health-related resources. Shelby County, TN, which includes the city of Memphis and the regional pediatric SCD treatment center at St. Jude Children's Research Hospital, is home to a large population of African Americans. PROCEDURE: We postulated that the regional birth prevalence of SCD in Shelby County, TN, would differ from national rates. Using data from 2002 to 2012, we estimated the birth prevalence of SCD and sickle cell trait (SCT) in Shelby County and evaluated the distribution of SCD cases by ZIP code of residence with geographic information systems (GIS). RESULTS: The prevalence of SCD in African Americans was 1/287 (95% confidence interval [CI]: 1/323, 1/256) live births, significantly higher than the nationally reported 1/350 -1/500. The prevalence of SCT in African Americans was 1/14.7 (95% CI: 1/15.0, 1/14.3) live births, significantly lower than the nationally reported 1/12. We found that 48% of the SCD cases resided in only six of the 37 residential ZIP codes, and using GIS mapping there were two clusters composed of two and four adjacent urban ZIP codes. SCT cases were also centered predominantly in the same two clusters, but slightly more dispersed. CONCLUSIONS: Recent Shelby County birth prevalence estimates differ substantially from national estimates with higher SCD and lower SCT than expected. Preliminary evidence suggests substantial clustering in two small geographic urban areas within Shelby County that may provide target areas for educational and outreach services.

Distance from an Urban Sickle Cell Center and its Effects on Routine Healthcare Management and Rates of Hospitalization.

The St. Jude Children's Research Hospital (St. Jude) comprehensive sickle cell center serves a 150 mile catchment radius around Memphis, TN, USA. Full travel expenses are provided for routine and acute care visits for sickle cell disease patients living 35 miles from St. Jude. We compared hospitalization rates to national estimates and assessed if driving distance was a barrier to sickle cell healthcare despite the travel reimbursement policy. We evaluated the associations between hospitalizations and routine clinic visits and distance from St. Jude using negative binomial models and we conducted bias analyses by Monte Carlo simulation. We followed 545 patients (2550 patient-years) aged 18 years with sickle cell disease (Hb SS only) from 2007 to 2012. The hospitalization rate per patient-year was 0.65 [95% CI (confidence interval): 0.62, 0.68), significantly lower than the national rate of 1.16 (95% CI: 1.14, 1.18). Children living 5 35 miles from St. Jude had 1.75 (95% CI: 1.41, 2.17) times the rate of hospitalization and 1.22 (95% CI: 1.07, 1.39) times the rate of clinic visits compared to those 35 miles. Bias analysis suggested that under-reporting could explain the observed difference in hospitalization rates if 30.0% of patients who lived 35 miles from the hospital under-reported six hospitalizations over 6 years. The hospitalization rate at St. Jude in children with sickle cell disease was lower than expected from national rates. Greater distance from the sickle cell center (4 35 miles) was associated with decreased hospitalization rates, despite the travel allowances that are provided for those who live 35 miles from the hospital.

Treatment-induced hearing loss and adult social outcomes in survivors of childhood CNS and non-CNS solid tumors: Results from the St. Jude Lifetime Cohort Study.

BACKGROUND: Survivors of childhood cancer who are treated with platinum-based chemotherapy and/or cranial radiation are at risk of treatment-induced hearing loss. However, the effects of such hearing loss on adult social attainment have not been well elucidated. METHODS: Adult survivors of pediatric central nervous system (CNS) solid tumors (180 survivors) and non-CNS solid tumors (226 survivors) who were treated with potentially ototoxic cancer therapy completed audiologic evaluations and questionnaires assessing their perception of social functioning and social attainment (ie, independent living, marriage, and employment). Audiograms were graded with the Chang ototoxicity grading scale. Analyses were stratified by tumor type (ie, CNS vs non-CNS). Multivariable logistic regression models were conducted with adjustment for age; sex; chronic health conditions; and, for the CNS group, IQ. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were reported. RESULTS: Serious hearing loss (that requiring a hearing aid or deafness) was detected in 36% of survivors of CNS tumors and 39% of survivors of non-CNS tumors. Serious hearing loss was associated with an increased risk of perceived negative impact in ≥1 areas of social functioning (survivors of non-CNS tumors: OR, 1.83 [95% CI, 1.00-3.34]). Among survivors of non-CNS tumors, serious hearing loss was associated with 2-fold increased risk of nonindependent living (OR, 2.19; 95% CI, 1.19-4.04) and unemployment or not graduating from high school (OR, 1.85; 95% CI, 1.00-3.34). CONCLUSIONS: A substantial proportion of adult survivors of childhood cancer treated with potentially ototoxic therapy have serious hearing loss. Treatment-induced hearing loss was found to be associated with reduced social attainment, both perceived and actual, in this study sample.

Factors associated with interhospital transfer of children with respiratory failure from level II to level I pediatric intensive care units.

PURPOSE: Of all sources of admission to level I pediatric intensive care units (PICUs), interhospital transfer admissions from level II PICUs carry the highest mortality and resource use burden. We sought to investigate factors associated with transfer of children with respiratory failure from level II to level I PICUs. METHODS: A case-control study was conducted among children with respiratory failure admitted to 6 level II PICUs between January 1, 1997, and December 31, 2007, with frequency matching of 466 nontransferred children (controls) to 187 transferred children (cases). RESULTS: Among 653 children, transferred children were younger and had more comorbidities. After multivariable analysis, transferred children were more likely to have comorbidities (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.36-2.98) and receive escalated care including high-frequency ventilation (OR, 2.57; 95% CI, 1.04-6.37) and surfactant therapy (OR, 5.33; 95% CI, 1.35-21.0). CONCLUSIONS: The study identified patient-level and process-of-care factors associated with transfer from level II to level I PICUs. These findings highlight the influence of escalated care on transfer decision making for critically ill children in respiratory failure.

Genetic and clinical factors associated with obesity among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort.

BACKGROUND: The objective of this study was to identify treatment and genetic factors associated with obesity among childhood cancer survivors. METHODS: Participants included 1996 survivors who previously received treatment for cancer at St. Jude Children's Research Hospital and who survived ≥10 years from diagnosis (median age at diagnosis, 7.2 years; median age at follow-up, 32.4 years). Obesity was defined as a body mass index ≥30 kg/m(2) . The factors associated with adult obesity were identified by subgroup-specific (cranial radiation [CRT] exposure status) multivariable logistic regression. Single nucleotide polymorphisms (SNPs) associated with obesity were identified by subgroup-specific, exploratory, genome-wide association analyses using a 2-stage resampling approach with a type I error rate of 5 × 10(-6) . RESULTS: Forty-seven percent of survivors who received CRT and 29.4% of those who did not receive CRT were obese at evaluation. In multivariable analyses, abdominal/pelvic radiation exposure was associated with decreased prevalence of obesity among survivors regardless of CRT status (P < .0001). The odds of obesity were increased among survivors who received CRT who had also received glucocorticoids (P = .014) or who were younger at diagnosis (P = .013). Among the survivors who had received CRT, 166 SNPs were associated with obesity. The strongest association was observed with reference SNP rs35669975 (P = 3.3 × 10(-8) ) on segment 33.3 of the long arm of chromosome 13 (13q33.3), approximately 30 kb downstream of FAM155A (family with sequence similarity 155, member A). SNPs within the glycine receptor α3 (GLRA3) gene and near the sex-determining region Y box 11 (SOX11) and cadherin 18 type 2 (CDH18) genes also were identified. These genes have been implicated in neural growth, repair, and connectivity. CONCLUSIONS: Obesity in childhood cancer survivors remains associated with previous exposure to CRT and glucocorticoids. Genetic variants related to neural connectivity may modify the risk of obesity among survivors who receive CRT. Validation of these findings in independent cohorts is required.

Prevalence of vitamin D deficiency in sickle cell disease: a systematic review.

Vitamin D deficiency has emerged as a public health focus in recent years and patients with sickle cell disease (SCD) reportedly have a high prevalence of the condition. Our objectives were to summarize definitions of vitamin D deficiency and insufficiency used in the literature, and to determine the prevalence and magnitude of each in patients with SCD through a systematic review conducted according to PRISMA guidelines. From a PubMed search, 34 potential articles were identified and 15 met eligibility criteria for inclusion. Definitions of deficiency and insufficiency varied greatly across studies making direct comparisons difficult. This review provides evidence to suggest that suboptimal vitamin D levels are highly prevalent among those with SCD, far more so than in comparable non-SCD patients or matched control populations. Defining deficiency as vitamin D < 20 ng/mL, prevalence estimates in SCD populations range from 56.4% to 96.4%. When compared with results from the population-based National Health and Nutrition Examination Survey, however, the general African American population appeared to have a similarly high prevalence of vitamin D deficiency. African American patients with and without SCD were both substantially higher than that of Caucasians. What remains to be determined is whether there are adverse health effects for patients with SCD because of concurrent vitamin D deficiency.