Reducing transfusion utilization for children with sickle cell anemia in sub-Saharan Africa with hydroxyurea: Analysis from the phase I/II REACH trial.

Children with sickle cell anemia (SCA) in Africa frequently require transfusions for SCA complications. Despite limited blood supplies, strategies to reduce their transfusion needs have not been widely evaluated or implemented. We analyzed transfusion utilization in children with SCA before and during hydroxyurea treatment. REACH (Realizing Effectiveness Across Continents with Hydroxyurea, NCT01966731) is a longitudinal Phase I/II trial of hydroxyurea in children with SCA from Angola, Democratic Republic of Congo, Kenya, and Uganda. After enrollment, children had a two-month pre-treatment screening period followed by 6 months of fixed-dose hydroxyurea (15-20 mg/kg/day), 18 months of dose escalation, and then stable dosing at maximum tolerated dose (MTD). Characteristics associated with transfusions were analyzed with univariate and multivariable models. Transfusion incidence rate ratios (IRR) across treatment periods were calculated. Among 635 enrolled children with 4124 person-years of observation, 258 participants (40.4%) received 545 transfusions. The transfusion rate per 100 person-years was 43.2 before hydroxyurea, 21.7 on fixed-dose, 14.5 during dose escalation, and 10.8 on MTD. During MTD, transfusion incidence was reduced by 75% compared to pre-treatment (IRR 0.25, 95% confidence interval [CI] 0.18-0.35, p < .0001), and by 50% compared to fixed dose (IRR 0.50, 95% CI 0.39-0.63, p < .0001). Hydroxyurea at MTD decreases transfusion utilization in African children with SCA. If widely implemented, universal testing and hydroxyurea treatment at MTD could potentially prevent 21% of all pediatric transfusions administered in sub-Saharan Africa. Increasing hydroxyurea access for SCA should decrease the transfusion burden and increase the overall blood supply.

Impact of dexamethasone on transplant-related mortality in pediatric patients: a multi-site, propensity score-weighted, retrospective assessment.

Dexamethasone use during hematopoietic cell transplant (HCT) conditioning varies between pediatric centers. This study aimed to estimate the difference in 1-year treatment-related mortality (TRM) between patients who did or did not receive dexamethasone during HCT conditioning. Secondary objectives were to estimate the difference between dexamethasone-exposed and dexamethasone-unexposed groups in 1-year event-free survival (EFS), time to neutrophil engraftment, acute graft-versus-host disease (aGVHD), and invasive fungal disease (IFD) at day + 100. This was a seven-site, international, retrospective cohort study. Patients < 18 years old undergoing their first allogeneic or autologous myeloablative HCT for hematologic malignancy or aplastic anemia between January 1, 2012, and July 31, 2017, were included. To control for potential confounders, propensity score weighting was used to calculate the standardized mean difference for all endpoints. Among 242 patients, 140 received dexamethasone during HCT conditioning and 102 did not. TRM was unaffected by dexamethasone exposure (1.7%; 95% CI - 7.4, 10.2%). Between-group differences in secondary outcomes were small. However, dexamethasone exposure significantly increased possible, probable, and proven IFD incidence (9.0%, 95% CI 0.8, 17.3%). TRM is not increased in pediatric patients who receive dexamethasone during HCT conditioning. Clinicians should consider potential IFD risk when selecting chemotherapy-induced vomiting prophylaxis for pediatric HCT patients.

Reliability and validity of proxy-SSPedi and mini-SSPedi in pediatric patients 2-7 years receiving cancer treatments.

BACKGROUND: Symptom Screening in Pediatrics Tool (SSPedi) was developed for symptom screening by children 8-18 years. Objectives were to evaluate the reliability and validity of proxy-SSPedi and self-report mini-SSPedi for younger children. METHODS: This multi-center study enrolled guardians of children 2-7 years receiving cancer treatments (proxy-SSPedi) and their children 4-7 years (mini-SSPedi). The two populations were: (1) More symptomatic group where children were receiving active cancer treatment and were in hospital or clinic for four consecutive days; and (2) Less symptomatic group where children were receiving maintenance therapy for acute lymphoblastic leukemia or had completed cancer therapy. Proxy-SSPedi or mini-SSPedi were completed with measures of mucositis, nausea, pain, quality of life and overall symptoms. Respondents in the more symptomatic group repeated proxy-SSPedi/mini-SSPedi and a global symptom change scale 3 days later. RESULTS: There were 402 guardians and 326 children included in the analysis. Test re-test reliability of proxy-SSPedi showed intraclass correlation coefficient (ICC) 0.83 (95% confidence interval (CI) 0.72-0.90). Mean difference in proxy-SSPedi between more and less symptomatic groups was 9.7 (95% CI 8.3-11.1). Proxy-SSPedi was responsive to change and hypothesized relationships between measures were observed. With a priori threshold ≥0.6, inter-rater ICC among all dyads and those 6-7 years were 0.54 (95% CI 0.45-0.62) and 0.62 (95% CI 0.50-0.71) respectively. Among participating children, other hypothesized reliability and validity thresholds were generally met. CONCLUSIONS: Proxy-SSPedi is reliable, valid and responsive in children 2-7 years old receiving cancer treatments. Mini-SSPedi can be used for children 6-7 years of age.

Functional Movement Screen Task Scores and Joint Range-of-motion: A Construct Validity Study.

Little is known about the construct validity of the Functional Movement Screen (FMS). We aimed to assess associations between FMS task scores and measures of maximum joint range-of-motion (ROM) among university varsity student-athletes from 4 sports (volleyball, basketball, ice hockey, and soccer). Athletes performed FMS tasks and had their maximum ankle, hip and shoulder ROM measured. Multivariable linear regression was used to estimate associations between FMS task scores and ROM measurements. 101 university student-athletes were recruited (52 W/49 M; mean age 20.4±1.9 years). In general, athletes with higher FMS task scores had greater ROM compared to those with lower task scores. For example, athletes who scored 2 on the FMS squat task had 4° (95% CI, 1° to 7°) more uni-articular ankle dorsiflexion ROM compared with those who scored 1, while those who scored 3 on the FMS squat task had 10° (4° to 17°) more uni-articular ankle dorsiflexion ROM compared with those who scored 1. Large variation in ROM measurements was observed. In sum, substantial overlap in joint ROM between groups of athletes with different FMS task scores weakens the construct validity of the FMS as an indicator of specific joint ROM.

Distinct maternal and fetal pregnancy outcomes in women with sickle cell disease can be predicted using routine clinical and laboratory data.

We aimed to identify risk factors for adverse outcomes in pregnancies of women with sickle cell disease (SCD) and develop risk prediction models. Models were derived from a retrospective cohort of pregnant women with SCD and constructed using generalised estimating equation logistic regression, with clustering by woman. Maternal event(s) consisted of acute anaemia; cardiac, pulmonary, hepatobiliary, musculoskeletal, skin, splenic, neurological or renal complications, multi-organ failure, venous thromboembolism, admission-requiring vaso-occlusive events (VOE), red cell transfusion, mortality or hypertensive disorder of pregnancy. Fetal events included preterm birth, small-for-gestational-age or perinatal mortality. Of 199 pregnancies, 71% and 45% resulted in adverse maternal and fetal outcomes respectively. Low first-trimester haemoglobin, admission-requiring VOE in the year before pregnancy, multiple transfusions before pregnancy, SCD genotype and previous cardiac complications predicted maternal risk. Younger age and SCD genotype allowed early prediction of fetal risk (model-F1). Adding maternal event(s) and high lactate dehydrogenase enabled re-assessment of fetal risk with advancing gestation (model-F2). Models were well calibrated and moderately discriminative for maternal outcome (c-statistic 0·81, cross-validated value 0·79) and fetal outcome (model-F1 c-statistic 0·68, cross-validated value 0·65; model-F2 c-statistic 0·72, cross-validated value 0·68). The models will allow early identification of women with SCD at high risk of adverse events, permitting early targeted interventions and ongoing fetal risk re-assessment enabling intensification of surveillance and optimisation of delivery timing.

Feeling scared or worried self-report in children receiving cancer treatments using the Symptom Screening in Pediatrics Tool (SSPedi).

INTRODUCTION: The objectives of this study were to describe reports of bother for feeling scared or worried among children with cancer and pediatric hematopoietic stem cell transplant (HSCT) recipients, and to identify factors associated with it. METHODS: We included children receiving cancer treatments who were 8-18 years of age. Three patient types were enrolled: inpatients receiving active cancer treatment, outpatients receiving maintenance acute lymphoblastic leukemia chemotherapy, and outpatients in survivorship. Amount of bother due to feeling scared or worried yesterday or today was self-reported using the Symptom Screening in Pediatrics Tool (SSPedi) on a 0-4 scale. Risk factors were evaluated using logistic regression. RESULTS: Among the 502 children included, 225 (45.0%) reported any degree of bother (score ≥ 1) and 29 (5.8%) reported severe bother (score ≥ 3) for feeling scared or worried. In multiple regression evaluating any bother, boys were less likely to be bothered (odds ratio (OR) 0.60, 95% confidence interval (CI) 0.41-0.87) and inpatients receiving active cancer treatment were more likely to be bothered compared to outpatients in survivorship (OR 3.58, 95% CI 2.00-6.52). The only factor associated with being severely bothered by feeling scared or worried was clinic visit or admission due to fever (OR 4.57, 95% CI 1.24-13.60). DISCUSSION: We found 45% of children receiving cancer treatments reported being bothered by feeling scared or worried. Girls and inpatients receiving active treatment experienced more bother of any degree, while visiting the hospital due to fever was associated with being severely bothered. Future work should identify interventions to prevent or alleviate this symptom.

Long-term morbidity and mortality in a Canadian post-transfusion hepatitis C cohort: Over 15 years of follow-up.

The Federal Government of Canada established a $1.1 billion compensation programme in 1999 to support individuals who acquired hepatitis C virus (HCV) through blood products between January 1986 and July 1990. We aimed to describe the morbidity and mortality of this unique post-transfusion cohort (n = 4550) followed for over 15 years from 2000 to 2016. The age-standardized mortality rates were compared with that of the Canadian general population and HCV cohorts from other countries. We evaluated all-cause mortality using Kaplan-Meier survival curves and HCV-related and unrelated mortality using competing risk models. The age-standardized all-cause and HCV-related mortality rates per 10 000 person-years were 127 (95% CI: 117-138) and 76 (95% CI: 69-85) for males, and 77 (95% CI: 69-87) and 43 (95% CI: 37-51) for females, respectively. The risk of death of the post-transfusion cohort was almost twice as high as the Canadian general population (rate ratio = 1.8; 95% CI: 1.7-1.9). All-cause, HCV-related and HCV-unrelated mortality were 20%, 12% and 8%, respectively at 15 years of follow-up. By comparison, HCV-related mortality rates per 10 000 person-years for population-based HCV cohorts varied from 18 and 11 in Australia to 65 and 43 in Scotland for males and females, respectively. We reported long-term follow-up data for the largest post-transfusion cohort in the literature. The all-cause mortality rates were markedly higher than that of the Canadian general population. We also showed that HCV-related mortality were greater compared to other HCV cohorts. This suggests that continued efforts to identify and treat post-transfusion HCV are warranted.

Development and utility assessment of a machine learning bloodstream infection classifier in pediatric patients receiving cancer treatments.

BACKGROUND: Objectives were to build a machine learning algorithm to identify bloodstream infection (BSI) among pediatric patients with cancer and hematopoietic stem cell transplantation (HSCT) recipients, and to compare this approach with presence of neutropenia to identify BSI. METHODS: We included patients 0-18 years of age at cancer diagnosis or HSCT between January 2009 and November 2018. Eligible blood cultures were those with no previous blood culture (regardless of result) within 7 days. The primary outcome was BSI. Four machine learning algorithms were used: elastic net, support vector machine and two implementations of gradient boosting machine (GBM and XGBoost). Model training and evaluation were performed using temporally disjoint training (60%), validation (20%) and test (20%) sets. The best model was compared to neutropenia alone in the test set. RESULTS: Of 11,183 eligible blood cultures, 624 (5.6%) were positive. The best model in the validation set was GBM, which achieved an area-under-the-receiver-operator-curve (AUROC) of 0.74 in the test set. Among the 2236 in the test set, the number of false positives and specificity of GBM vs. neutropenia were 508 vs. 592 and 0.76 vs. 0.72 respectively. Among 139 test set BSIs, six (4.3%) non-neutropenic patients were identified by GBM. All received antibiotics prior to culture result availability. CONCLUSIONS: We developed a machine learning algorithm to classify BSI. GBM achieved an AUROC of 0.74 and identified 4.3% additional true cases in the test set. The machine learning algorithm did not perform substantially better than using presence of neutropenia alone to predict BSI.

Associations between self-reported physical activity, quality of life, and emotional well-being in men with prostate cancer on active surveillance.

OBJECTIVE: The relationship between physical activity (PA) and quality of life (QOL) relative to active treatment for prostate cancer (PCa) has been well-studied; however, little is known about this relationship during active surveillance (AS). Moreover, whether PA is associated with better emotional well-being (EWB) in men with low-risk PCa requires further investigation. Accordingly, we examined the association between self-reported PA and the average change in QOL and EWB over time during AS. METHODS: A total of 630 men on AS were included in this retrospective, longitudinal study from AS initiation until AS discontinuation. Generalized estimated equations were used to determine the association between self-reported PA (independent variable) and QOL and EWB (dependent variables) over time, adjusting for participants' age. RESULTS: QOL was higher over time in active ( ß^ (95%CI) = 1.14 (0.11, 2.16), P = .029) and highly active participants ( ß^ (95%CI) = 1.62 (0.58, 2.67), P = .002) compared to their inactive counterparts. Highly active participants had 55% greater odds of experiencing high EWB relative to inactive participants (OR (95%CI) = 1.55 (1.11, 2.16), P = .010). In men with low EWB at baseline (median = 3 months after diagnosis), the highest levels of PA (>1000 metabolic equivalent-minutes per week) were associated with high EWB over time (OR (95%CI) = 2.17 (1.06, 4.46), P = .034). CONCLUSIONS: These data further support the importance of PA as a supportive care strategy for men on AS. Our findings suggest that engaging in higher volumes of PA post-diagnosis may be beneficial particularly for men exhibiting low emotional well-being early on during AS.

Feasibility of a randomized controlled trial of symptom screening and feedback to healthcare providers compared with standard of care using the SPARK platform.

PURPOSE: Supportive care Prioritization, Assessment and Recommendations for Kids (SPARK) is a web-based application that enables symptom screening and access to clinical practice guidelines for symptom management. Objective was to determine the feasibility of a randomized trial of daily symptom screening for 5 days among children receiving cancer treatments. METHODS: We included English-speaking pediatric cancer and hematopoietic stem cell transplantation (HSCT) patients who were 8-18 years of age at enrollment and who were expected to be in the hospital or in clinic daily for five consecutive days. We randomized children to either undergo daily symptom screening with symptom reports provided to the healthcare team using the SPARK vs. standard of care. The primary endpoint was feasibility, defined as being able to enroll at least 30 participants within 1 year, and among those randomized to intervention, at least 75% completing symptom screening on at least 60% of on-study days. RESULTS: From July 2018 to November 2018, we enrolled and randomized 30 participants. The median age at enrollment was 12.5 (range 8-18) years. Among the intervention group, the median number of days Symptom Screening in Pediatrics Tool (SSPedi) was completed at least once was 5 (range 4 to 5), with one participant missing 1 day of symptom screening. Among all participants, baseline and day 5 SSPedi scores were obtained in 29/30 participants. CONCLUSION: A randomized trial of the SPARK with daily symptom screening for 5 days was feasible. It is now appropriate to proceed toward a definitive multi-center trial to test the efficacy of SPARK to improve symptom control.

Influence of physical activity on active surveillance discontinuation in men with low-risk prostate cancer.

PURPOSE: Epidemiologic data suggest that high levels of physical activity (PA) may reduce the risk of disease progression in men with prostate cancer (PCa), but it is unknown whether PA can delay the requirement for definitive treatment for those on active surveillance (AS). We investigated the influence of PA post-diagnosis on AS discontinuation in men with low-risk disease. METHODS: The effect of PA on the time to AS discontinuation was assessed in 421 patients, of whom 107 underwent additional PCa treatment over a median of 2.5 years. RESULTS: Using Cox regression models, we found that PA was not significantly associated with time to curative treatment initiation. Prostate-specific antigen (PSA) most proximal to AS initiation (HR, 1.11; 95% CI 1.03 to 1.21) and the number of positive cores (HR, 1.34; 95% CI 1.12 to 1.61) at diagnosis were associated with a significantly increased risk of discontinuing AS. CONCLUSION: Our findings suggest that PA during AS for PCa does not significantly influence time to curative treatment.

Association between allopurinol and cardiovascular outcomes and all-cause mortality in diabetes: A retrospective, population-based cohort study.

AIM: To assess the association between allopurinol and mortality and cardiovascular outcomes in an allopurinol-treated diabetes cohort. MATERIALS AND METHODS: We conducted a population-based retrospective cohort study in Ontario, Canada. Eligible subjects were ≥ 66 years old with diabetes and a first prescription for allopurinol between 1 April, 2002 and 31 March, 2012 and were followed until 31 March, 2016. The primary outcome was a composite: all-cause mortality, non-fatal cardiovascular event (myocardial infarction, revascularization procedure, or stroke) or congestive heart failure (CHF). Secondary outcomes were components of the primary outcome and pneumonia as a negative tracer. Allopurinol was modelled as time-varying exposed versus unexposed, daily dose category and cumulative dose using sex-specific multivariable Cox proportional hazards models. RESULTS: Over a median follow-up of 4.65 years (interquartile range 1.79-7.81), 16 266/23 103 males and 10 571/15 313 females experienced the primary outcome. Allopurinol was associated with a reduction in the primary outcome [adjusted hazard ratios (aHR) 0.77 (95% confidence interval 0.75-0.80) and 0.81 (0.78-0.84) for males and females, respectively], driven by marked reductions in all-cause mortality and modest reductions in cardiovascular events/CHF. There was no effect of cumulative allopurinol dose on any outcome, and allopurinol was also associated with reduced risk of pneumonia in males [aHR 0.88 (0.83, 0.93)]. CONCLUSIONS: Allopurinol was associated with reduced mortality and cardiovascular outcomes. However, lack of cumulative dose effect and a positive tracer outcome in males suggests residual bias. Future research assessing whether allopurinol prevents vascular complications in diabetes requires a clinical trial.

Severely bothersome fatigue in children and adolescents with cancer and hematopoietic stem cell transplant recipients.

BACKGROUND: Objectives were to describe bothersome fatigue in children with cancer and hematopoietic stem cell (HSCT) recipients and to identify factors associated with severely bothersome fatigue. METHODS: We included children ages 8-18 years treated for cancer or HSCT recipients from three groups: [1] receiving active cancer treatment and admitted to hospital for at least 3 days, [2] attending outpatient clinic for acute lymphoblastic leukemia maintenance therapy, and [3] attending outpatient clinic following treatment completion. Fatigue was measured using the Symptom Screening in Pediatrics Tool (SSPedi); severely bothersome fatigue was defined as a lot or extremely bothersome fatigue (score of 3-4 on 0-4 scale). Factors associated with severely bothersome fatigue were examined using univariate and multiple logistic regression. RESULTS: Of 502 children included, 414 (82.5%) reported some degree of bothersome fatigue (scores 1-4), and 123 (24.5%) reported severely bothersome fatigue (score 3 or 4). In multiple regression analysis, factors significantly associated with severely bothersome fatigue were child age 11-14 and 15-18 years vs 8-10 years (odds ratio (OR) 2.11, 95% confidence interval (CI) 1.21-3.77 and OR 2.96, 95% CI 1.66-5.44), and inpatients receiving cancer treatment vs outpatients who had completed therapy (OR 3.85, 95% CI 2.17-7.27). CONCLUSIONS: We found that 82.5% of children with cancer or HSCT recipients reported bothersome fatigue and 24.5% of children reported severely bothersome fatigue. Risk factors for severely bothersome fatigue were older age and inpatients receiving active cancer treatment. Future work should evaluate systematic symptom screening in clinical practice and apply interventions to reduce fatigue.

Taste changes in children with cancer and hematopoietic stem cell transplant recipients.

BACKGROUND: Objectives were to describe bothersome self-reported changes in taste in pediatric oncology and hematopoietic stem cell (HSCT) patients and to identify patient and treatment-related factors associated with bothersome taste changes. METHODS: We prospectively enrolled children and adolescents with cancer or pediatric HSCT recipients 8-18 years of age from three groups: inpatients receiving cancer treatments; outpatients in maintenance therapy for acute lymphoblastic leukemia (ALL); and outpatients in survivorship. Bothersome changes in taste was self-reported using the Symptom Screening in Pediatrics Tool (SSPedi); nausea was self-reported using the Pediatric Nausea Assessment Tool (PeNAT). RESULTS: Among the 502 children included, 226 (45.0%) reported bothersome taste changes and 48 (9.6%) reported severely bothersome taste changes. In multiple regression, factors independently associated with severely bothersome taste changes were: inpatients receiving cancer treatments vs outpatients in survivorship (odds ratio (OR) 12.28, 95% confidence interval (CI) 2.50-222.27), ALL in maintenance vs outpatients in survivorship (OR 7.43, 95% CI 1.06-147.77), current nausea (OR 1.59, 95% CI 1.04-2.42), vomiting (OR 2.18, 95% CI 1.06-4.38), and first language not English (OR 2.09, 95% CI 0.97-4.28). CONCLUSIONS: We found that 45% of children with cancer and pediatric HSCT recipients reported bothersome changes in taste and these were severely bothersome in 9.6% of children. Inpatients receiving cancer treatment, those experiencing more nausea and vomiting and children whose first language was not English were at greater risk of severely bothersome changes in taste. Future work should evaluate systematic symptom screening in clinical practice and identify interventions focused on addressing bothersome taste changes.

Improving bone health in men with prostate cancer receiving androgen deprivation therapy: Results of a randomized phase 2 trial.

BACKGROUND: Strategies to improve bone health care in men receiving androgen deprivation therapy (ADT) are not consistently implemented. The authors conducted a phase 2 randomized controlled trial of 2 education-based models-of-care interventions to determine their feasibility and ability to improve bone health care. METHODS: A single-center parallel-group randomized controlled trial of men with prostate cancer who were receiving ADT was performed. Participants were randomized 1:1:1 to 1) a patient bone health pamphlet and brief recommendations for their family physician (BHP+FP); 2) a BHP and support from a bone health care coordinator (BHP+BHCC); or 3) usual care. The primary efficacy outcome was receipt of a bone mineral density (BMD) test within 6 months. Secondary efficacy outcomes included guideline-appropriate calcium and vitamin D use and bisphosphonate prescriptions for men at high fracture risk. Feasibility endpoints included recruitment, retention, satisfaction, contamination, and outcome capture. The main analysis used logistic regression with a 1-sided P of .10. The trial is registered at ClinicalTrials.gov (identifier NCT02043236). RESULTS: A total of 119 men were recruited. The BHP+BHCC strategy was associated with a greater percentage of men undergoing a BMD test compared with the usual-care group (78% vs 36%; P<.001). BMD ordering also was found to be increased with the BHP+FP strategy (58% vs 36%; P = .047). Both strategies were associated with higher percentages of patients using calcium and vitamin D, but only the BHP+FP arm was statistically significant (P = .039). No men were detected to be at high fracture risk. All but one feasibility endpoint was met. CONCLUSIONS: Educational strategies to improve bone health care appear feasible and are associated with improved BMD ordering in men receiving ADT. Cancer 2018;124:1132-40. © 2017 American Cancer Society.

Realizing effectiveness across continents with hydroxyurea: Enrollment and baseline characteristics of the multicenter REACH study in Sub-Saharan Africa.

Despite its well-described safety and efficacy in the treatment of sickle cell anemia (SCA) in high-income settings, hydroxyurea remains largely unavailable in sub-Saharan Africa, where more than 75% of annual SCA births occur and many comorbidities exist. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) is a prospective, Phase I/II open-label trial of hydroxyurea designed to evaluate the feasibility, safety, and benefits of hydroxyurea treatment for children with SCA in four sub-Saharan African countries. Following comprehensive training of local research teams, REACH was approved by local Ethics Committees and achieved full enrollment ahead of projections with 635 participants enrolled over a 30-month period, despite half of families living >12 km from their clinical site. At enrollment, study participants (age 5.4 ± 2.4 years) had substantial morbidity, including a history of vaso-occlusive pain (98%), transfusion (68%), malaria (85%), and stroke (6%). Significant differences in laboratory characteristics were noted across sites, with lower hemoglobin concentrations (P < .01) in Angola (7.2 ± 1.0 g/dL) and the DRC (7.0 ± 0.9 g/dL) compared to Kenya (7.4 ± 1.1 g/dL) and Uganda (7.5 ± 1.1 g/dL). Analysis of known genetic modifiers of SCA demonstrated a high frequency of α-thalassemia (58.4% with at least a single α-globin gene deletion) and G6PD deficiency (19.7% of males and 2.4% of females) across sites. The CAR ß-globin haplotype was present in 99% of participants. The full enrollment to REACH confirms the feasibility of conducting high-quality SCA research in Africa; this study will provide vital information to guide safe and effective dosing of hydroxyurea for children with SCA living in Africa.

Chiropractic spinal manipulation and the risk for acute lumbar disc herniation: a belief elicitation study.

PURPOSE: Chiropractic spinal manipulation treatment (SMT) is common for back pain and has been reported to increase the risk for lumbar disc herniation (LDH), but there is no high quality evidence about this. In the absence of good evidence, clinicians can have knowledge and beliefs about the risk. Our purpose was to determine clinicians' beliefs regarding the risk for acute LDH associated with chiropractic SMT. METHODS: Using a belief elicitation design, 47 clinicians (16 chiropractors, 15 family physicians and 16 spine surgeons) that treat patients with back pain from primary and tertiary care practices were interviewed. Participants' elicited incidence estimates of acute LDH among a hypothetical group of patients with acute low back pain treated with and without chiropractic SMT, were used to derive the probability distribution for the relative risk (RR) for acute LDH associated with chiropractic SMT. RESULTS: Chiropractors expressed the most optimistic belief (median RR 0.56; IQR 0.39-1.03); family physicians expressed a neutral belief (median RR 0.97; IQR 0.64-1.21); and spine surgeons expressed a slightly more pessimistic belief (median RR 1.07; IQR 0.95-1.29). Clinicians with the most optimistic views believed that chiropractic SMT reduces the incidence of acute LDH by about 60% (median RR 0.42; IQR 0.29-0.53). Those with the most pessimistic views believed that chiropractic SMT increases the incidence of acute LDH by about 30% (median RR 1.29; IQR 1.11-1.59). CONCLUSIONS: Clinicians' beliefs about the risk for acute LDH associated with chiropractic SMT varied systematically across professions, in spite of a lack of scientific evidence to inform these beliefs. These probability distributions can serve as prior probabilities in future Bayesian analyses of this relationship.

Chiropractic care and risk for acute lumbar disc herniation: a population-based self-controlled case series study.

PURPOSE: Chiropractic care is popular for low back pain, but may increase the risk for acute lumbar disc herniation (LDH). Low back pain is a common early (prodromal) symptom of LDH and commonly precedes LDH diagnosis. Our objective was to investigate the association between chiropractic care and acute LDH with early surgical intervention, and contrast this with the association between primary care physician (PCP) care and acute LDH with early surgery. METHODS: Using a self-controlled case series design and population-based healthcare databases in Ontario, Canada, we investigated all adults with acute LDH requiring emergency department (ED) visit and early surgical intervention from April 1994 to December 2004. The relative incidence of acute LDH with early surgery in exposed periods after chiropractic visits relative to unexposed periods was estimated within individuals, and compared with the relative incidence of acute LDH with early surgery following PCP visits. RESULTS: 195 cases of acute LDH with early surgery (within 8 weeks) were identified in a population of more than 100 million person-years. Strong positive associations were found between acute LDH and both chiropractic and PCP visits. The risk for acute LDH with early surgery associated with chiropractic visits was no higher than the risk associated with PCP visits. CONCLUSIONS: Both chiropractic and primary medical care were associated with an increased risk for acute LDH requiring ED visit and early surgery. Our analysis suggests that patients with prodromal back pain from a developing disc herniation likely seek healthcare from both chiropractors and PCPs before full clinical expression of acute LDH. We found no evidence of excess risk for acute LDH with early surgery associated with chiropractic compared with primary medical care.

Bone Health and Bone-Targeted Therapies for Nonmetastatic Prostate Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Bone health is a significant concern in men with prostate cancer. PURPOSE: To evaluate the effectiveness of drug, supplement, and lifestyle interventions aimed at preventing fracture, improving bone mineral density (BMD), or preventing or delaying osteoporosis in men with nonmetastatic prostate cancer. DATA SOURCES: Ovid MEDLINE (1946 to 19 January 2017), EMBASE (1980 to 18 January 2017), and the Cochrane Database of Systematic Reviews (19 January 2017). STUDY SELECTION: Randomized trials and systematic reviews of trials that were published in English; involved men with nonmetastatic prostate cancer; and compared bone-targeted therapies with placebo, usual care, or other active treatments. DATA EXTRACTION: Two reviewers independently extracted study characteristics and assessed study risk of bias for each outcome. DATA SYNTHESIS: Two systematic reviews and 28 reports of 27 trials met inclusion criteria. All trials focused on men with nonmetastatic prostate cancer who were initiating or continuing androgen deprivation therapy (ADT). Bisphosphonates were effective in increasing BMD, but no trial was sufficiently powered to detect reduction in fractures. Denosumab improved BMD and reduced the incidence of new radiographic vertebral fractures in 1 high-quality trial. No trials compared calcium or vitamin D versus placebo. Three lifestyle intervention trials did not show a statistically significant difference in change in BMD between exercise and usual care. LIMITATIONS: Most trials were of moderate quality. Only 2 randomized controlled trials were designed to examine fracture outcomes. Potential harms of treatments were not evaluated. CONCLUSION: Both bisphosphonates and denosumab improve BMD in men with nonmetastatic prostate cancer who are receiving ADT. Denosumab also reduces risk for radiographic vertebral fractures, based on 1 trial. More trials studying fracture outcomes are needed in this population. PRIMARY FUNDING SOURCE: Program in Evidence-Based Care.

Effect of a Pediatric Early Warning System on All-Cause Mortality in Hospitalized Pediatric Patients: The EPOCH Randomized Clinical Trial.

Importance: There is limited evidence that the use of severity of illness scores in pediatric patients can facilitate timely admission to the intensive care unit or improve patient outcomes. Objective: To determine the effect of the Bedside Paediatric Early Warning System (BedsidePEWS) on all-cause hospital mortality and late admission to the intensive care unit (ICU), cardiac arrest, and ICU resource use. Design, Setting, and Participants: A multicenter cluster randomized trial of 21 hospitals located in 7 countries (Belgium, Canada, England, Ireland, Italy, New Zealand, and the Netherlands) that provided inpatient pediatric care for infants (gestational age ≥37 weeks) to teenagers (aged ≤18 years). Participating hospitals had continuous physician staffing and subspecialized pediatric services. Patient enrollment began on February 28, 2011, and ended on June 21, 2015. Follow-up ended on July 19, 2015. Interventions: The BedsidePEWS intervention (10 hospitals) was compared with usual care (no severity of illness score; 11 hospitals). Main Outcomes and Measures: The primary outcome was all-cause hospital mortality. The secondary outcome was a significant clinical deterioration event, which was defined as a composite outcome reflecting late ICU admission. Regression analyses accounted for hospital-level clustering and baseline rates. Results: Among 144 539 patient discharges at 21 randomized hospitals, there were 559 443 patient-days and 144 539 patients (100%) completed the trial. All-cause hospital mortality was 1.93 per 1000 patient discharges at hospitals with BedsidePEWS and 1.56 per 1000 patient discharges at hospitals with usual care (adjusted between-group rate difference, 0.01 [95% CI, -0.80 to 0.81 per 1000 patient discharges]; adjusted odds ratio, 1.01 [95% CI, 0.61 to 1.69]; P = .96). Significant clinical deterioration events occurred during 0.50 per 1000 patient-days at hospitals with BedsidePEWS vs 0.84 per 1000 patient-days at hospitals with usual care (adjusted between-group rate difference, -0.34 [95% CI, -0.73 to 0.05 per 1000 patient-days]; adjusted rate ratio, 0.77 [95% CI, 0.61 to 0.97]; P = .03). Conclusions and Relevance: Implementation of the Bedside Paediatric Early Warning System compared with usual care did not significantly decrease all-cause mortality among hospitalized pediatric patients. These findings do not support the use of this system to reduce mortality. Trial Registration: clinicaltrials.gov Identifier: NCT01260831.