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Purpose: The purpose of this study was to determine if a nighttime home monitoring system, designed to track the movements of a care recipient with dementia, would relieve worry and improve sleep in caregivers of persons with dementia. Design and Methods: In this controlled clinical trial, 49 dementia caregivers were followed for up to 1 year. Sleep was measured for 7-day intervals at nine points in time using actigraphy and a sleep diary. Findings: Although the experimental caregivers generally reported that the system was “of great help” in relieving worry about nighttime activity, no significant group differences were found using multilevel modeling analyses. With regard to total sleep time, time awake after sleep onset, and sleep quality, multilevel models did not demonstrate any changes in sleep between groups, either averaged over time or for the interaction of group and time. Conclusions: Since previous analysis of our qualitative data suggested improvements in caregiver worry and sleep, problems other than night awakenings may be perpetuating the sleep problem. Future studies should include testing of multimodal sleep interventions. Clinical Relevance: Caregivers have high amounts of unwanted wake time during the night and additional research is needed to identify effective interventions to improve their sleep. [ABSTRACT FROM AUTHOR]

BACKGROUND: The Beck Depression Inventory II (BDI-II) is considered a gold standard for identifying depression in adults. Validity of the BDI-II has been documented in diverse populations using exploratory factor analysis (EFA), although no findings have been reported exclusively among lower income women. Among EFA findings, the factor structure of the BDI-II has been inconsistent, with cognitive, affective, and somatic domains emerging differentially within factors across studies. This, in conjunction with concerns around the confounding of depressive symptoms as measured by the BDI-II and other illness states, has led researchers to examine more complex factor structures using confirmatory factor analysis (CFA). OBJECTIVE: The purpose of this study was to evaluate the factor structure of the BDI-II using both EFA and CFA among low-income women. METHODS: After EFA with Promax rotation, CFA testing was conducted on several structural models with two randomly split subsamples of 108 and 200 women going through a Welfare Transition Program. RESULTS: A two-factor structure was indicated by EFA, with the cognitive and affective domains represented in Factor 1 and somatic items comprising Factor 2. CFA revealed a general factor model, with General Depression and residual Cognitive and Somatic factors, best fit to the data on the basis of several indices (root mean square error of approximation = 0.05; standardized root mean square residual = 0.05; weighted root mean square residual = 0.69; comparative fit index = .98; and Tucker-Lewis index = .99) and model difference tests of significance (four comparisons: all chi values >24.9, all p values < .001). DISCUSSION: Measurement using BDI-II is best represented by a complex factor structure among low-income women and is consistent with findings in other populations. Additional consideration for how a general model factor structure provides potentially new directions for depression measurement may advance science in several areas. [ABSTRACT FROM AUTHOR]

Limited prognostic factors have been associated with overall survival (OS) post-relapse in childhood Acute Lymphoblastic Leukemia (ALL). Patients enrolled on 12 Children's Oncology Group frontline ALL trials (1996-2014) were analyzed to assess for additional prognostic factors associated with OS post-relapse. Among 16,115 patients, 2053 (12.7%) relapsed. Relapse rates were similar for B-ALL (12.5%) and T-ALL (11.2%) while higher for infants (34.2%). Approximately 50% of B-ALL relapses occurred late (≥36 months) and 72.5% involved the marrow. Conversely, 64.8% of T-ALL relapses occurred early (<18 months) and 47.1% involved the central nervous system. The 5-year OS post-relapse for the entire cohort was 48.9 ± 1.2%; B-ALL:52.5 ± 1.3%, T-ALL:35.5 ± 3.3%, and infant ALL:21.5 ± 3.9%. OS varied by early, intermediate and late time-to-relapse; 25.8 ± 2.4%, 49.5 ± 2.2%, and 66.4 ± 1.8% respectively for B-ALL and 29.8 ± 3.9%, 33.3 ± 7.6%, 58 ± 9.8% for T-ALL. Patients with ETV6::RUNX1 or Trisomy 4 + 10 had median time-to-relapse of 43 months and higher OS post-relapse 74.4 ± 3.1% and 70.2 ± 3.6%, respectively. Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short median time-to-relapse (12.5-18 months) and poor OS post-relapse (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%). Site-of-relapse varied by cytogenetic subtype. This large dataset provided the opportunity to identify risk factors for OS post-relapse to inform trial design and highlight populations with dismal outcomes post-relapse., (© 2024. The Author(s).)

Objectives: Survivors of childhood B-acute lymphoblastic leukemia (B-ALL) are at risk for difficulties with attention and executive functioning (EF) as a late effect of treatment. The present study aimed to identify treatment and demographic factors associated with risk for difficulties with EF in youth treated for high-risk B-ALL., Method: Children and adolescents with B-ALL treated on Children's Oncology Group (COG) protocol AALL0232 were randomized to high-dose or escalating-dose methotrexate (MTX), and either dexamethasone or prednisone during the induction phase. Neuropsychological functioning was evaluated via protocol AALL06N1, including performance-based and parent-report measures, for 177 participants (57% female, 81% white; mean age at diagnosis = 8.4 years; SD = 5.0) 8-24 months following treatment completion., Results: Mean scores for all attention and EF measures were within the average range, with no significant differences as a function of MTX delivery or steroid treatment (all p > 0.05). In multivariable models, participants with US public insurance exhibited significantly greater parent-reported EF difficulties than those with US private or non-US insurance (p ≤ 0.05). Additionally, participants diagnosed under 10 years of age performed significantly more poorly on measures of attention (i.e., continuous performance task, p ≤ 0.05) and EF (i.e., verbal fluency and tower planning task, p ≤ 0.05)., Conclusions: For survivors of pediatric B-ALL, treatment-related factors were not associated with attention or EF outcomes. In contrast, outcomes varied by demographic characteristics, including age and insurance type, an indicator of economic hardship. Future research is needed to more directly assess the contribution of socioeconomic status on cognitive outcomes in survivors., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Purpose: Many children treated for ALL develop long-term neurocognitive impairments. Increased risk of these impairments is associated with treatment and demographic factors. Exposure to anesthesia is an additional possible risk factor. This study evaluated the impact of cumulative exposure to anesthesia on neurocognitive outcomes among a multicenter cohort of children with ALL., Methods: This study was embedded in AALL1131, a Children's Oncology Group phase III trial for patients with high-risk B-ALL. In consenting patients age 6-12 years, prospective uniform assessments of neurocognitive function were performed during and at 1 year after completion of therapy. Exposure to all episodes of anesthetic agents was abstracted. Multivariable linear regression models determined associations of cumulative anesthetic agents with the primary neurocognitive outcome reaction time/processing speed (age-normed) at 1 year off therapy, adjusting for baseline neurocognitive score, age, sex, race/ethnicity, insurance status (as a proxy for socioeconomic status), and leukemia risk group., Results: One hundred and forty-four children, 76 (52.8%) males, mean age of 9.1 (min-max, 6.0-12.0) years at diagnosis, underwent a median of 27 anesthetic episodes (min-max, 1-37). Almost all patients were exposed to propofol (140/144, 97.2%), with a mean cumulative dose of 112.3 mg/kg. One year after therapy, the proportion of children with impairment ( Z -score ≤-1.5) was significantly higher compared with a normative sample. In covariate-adjusted multivariable analysis, cumulative exposure to propofol was associated with a 0.05 Z -score decrease in reaction time/processing speed per each 10 mg/kg propofol exposure ( P = .03)., Conclusion: In a multicenter and uniformly treated cohort of children with B-ALL, cumulative exposure to propofol was an independent risk factor for impairment in reaction time/processing speed 1 year after therapy. Anesthesia exposure is a modifiable risk, and opportunities to minimize propofol use should be considered.

Infants less than 1 year old diagnosed with KMT2A-rearranged (KMT2A-r) acute lymphoblastic leukemia (ALL) are at high risk of remission failure, relapse, and death due to leukemia, despite intensive therapies. Infant KMT2A-r ALL blasts are characterized by DNA hypermethylation. Epigenetic priming with DNA methyltransferase inhibitors increases the cytotoxicity of chemotherapy in preclinical studies. The Children's Oncology Group trial AALL15P1 tested the safety and tolerability of five days of azacitidine immediately prior to the start of chemotherapy on day six, in four post-induction chemotherapy courses for infants with newly diagnosed KMT2A-r ALL. The treatment was welltolerated, with only two of 31 evaluable patients (6.5%) experiencing dose-limiting toxicity. Whole genome bisulfite sequencing of peripheral blood mononuclear cells (PBMCs) demonstrated decreased DNA methylation in 87% of samples tested following five days of azacitidine. Event-free survival was similar to prior studies of newly diagnosed infant ALL. Azacitidine is safe and results in decreased DNA methylation of PBMCs in infants with KMT2A-r ALL, but the incorporation of azacitidine to enhance cytotoxicity did not impact survival. Clinicaltrials.gov identifier: NCT02828358.

Current strategies to treat pediatric acute lymphoblastic leukemia rely on risk stratification algorithms using categorical data. We investigated whether using continuous variables assigned different weights would improve risk stratification. We developed and validated a multivariable Cox model for relapse-free survival (RFS) using information from 21199 patients. We constructed risk groups by identifying cutoffs of the COG Prognostic Index (PI COG ) that maximized discrimination of the predictive model. Patients with higher PI COG have higher predicted relapse risk. The PI COG reliably discriminates patients with low vs. high relapse risk. For those with moderate relapse risk using current COG risk classification, the PI COG identifies subgroups with varying 5-year RFS. Among current COG standard-risk average patients, PI COG identifies low and intermediate risk groups with 96% and 90% RFS, respectively. Similarly, amongst current COG high-risk patients, PI COG identifies four groups ranging from 96% to 66% RFS, providing additional discrimination for future treatment stratification. When coupled with traditional algorithms, the novel PI COG can more accurately risk stratify patients, identifying groups with better outcomes who may benefit from less intensive therapy, and those who have high relapse risk needing innovative approaches for cure., (© 2024. The Author(s).)

Chemotherapy-induced peripheral neuropathy (CIPN), a common condition in children with acute lymphoblastic leukemia, can be challenging to diagnose. Using data from Children's Oncology Group AALL0932 physical function study, we sought to determine if parent/guardian proxy-reported responses from the Pediatric Outcomes Data Collection Instrument could identify children with motor or sensory CIPN diagnosed by physical/occupational therapists (PT/OT). Four variables moderately discriminated between children with and without motor CIPN (c-index 0.76, 95% confidence interval [CI]: 0.64-0.84), but sensory and optimism-corrected models had weak discrimination (c-index sensory models 0.65, 95% CI: 0.54-0.74). New proxy-report measures are needed to identify children with PT/OT diagnosed CIPN., (© 2023 Wiley Periodicals LLC.)

There is considerable debate surrounding the choice of methods to estimate information fraction for futility monitoring in a randomized non-inferiority maximum duration trial. This question was motivated by a pediatric oncology study that aimed to establish non-inferiority for two primary outcomes. While non-inferiority was determined for one outcome, the futility monitoring of the other outcome failed to stop the trial early, despite accumulating evidence of inferiority. For a one-sided trial design for which the intervention is inferior to the standard therapy, futility monitoring should provide the opportunity to terminate the trial early. Our research focuses on the Total Control Only (TCO) method, which is defined as a ratio of observed events to total events exclusively within the standard treatment regimen. We investigate its properties in stopping a trial early in favor of inferiority. Simulation results comparing the TCO method with alternative methods, one based on the assumption of an inferior treatment effect (TH0), and the other based on a specified hypothesis of a non-inferior treatment effect (THA), were provided under various pediatric oncology trial design settings. The TCO method is the only method that provides unbiased information fraction estimates regardless of the hypothesis assumptions and exhibits a good power and a comparable type I error rate at each interim analysis compared to other methods. Although none of the methods is uniformly superior on all criteria, the TCO method possesses favorable characteristics, making it a compelling choice for estimating the information fraction when the aim is to reduce cancer treatment-related adverse outcomes., (© 2023 John Wiley & Sons Ltd.)

Purpose: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer diagnosis. Cognitive late effects develop in 20%-40% of ALL survivors, but the course of declines is unclear. The aim of this paper is to characterize cognitive functioning, and its association with patient-reported outcomes, early in treatment., Patients and Methods: A total of 483 children with high-risk ALL, aged 6-12 years at diagnosis, consented to the neurocognitive study embedded in a prospective therapeutic trial, Children's Oncology Group (COG) AALL1131. A computerized neurocognitive battery (Cogstate) was administered 3 months post diagnosis assessing reaction time, visual attention, working memory, visual learning, and executive functioning. Parent-reported executive functioning and patient-reported physical symptoms were also collected., Results: Data from 390 participants (mean age at diagnosis = 9.2 years, 55.4% male) were obtained. Relatively few patients reported pain (16.0%) or nausea (22.6%), but a majority (68.5%) reported feeling at least some fatigue at testing. Mean Cogstate Z-scores were within normal limits across tasks; however, rates of impairment (Z-scores ≤ -1.5) for reaction time, working memory, visual learning, and visual attention were all higher than expected compared to the standardization sample. Patients reporting fatigue were significantly more likely to have impaired reaction time and visual attention compared to those reporting no fatigue., Conclusion: Findings support feasibility of computerized cognitive assessments and suggest higher-than-expected rates of impaired cognitive performance early during treatment for pediatric ALL, notably within 3 months of diagnosis, suggesting intervention efforts may be indicated. These results also highlight acute factors that may impact reliability of "baseline" assessments conducted soon after diagnosis., (© 2023 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

We measured minimal residual disease (MRD) by multiparameter flow cytometry at three time points (TP) in 117 infants with KMT2A (lysine [K]-specific methyltransferase 2A)-rearranged and 58 with KMT2A-germline acute lymphoblastic leukemia (ALL) on Children's Oncology Group AALL0631 study. For KMT2A-rearranged patients, 3-year event-free survival (EFS) by MRD-positive (≥0.01%) versus MRD-negative (<0.01%) was: TP1: 25% (±6%) versus 49% (±7%; p = .0009); TP2: 21% (±8%) versus 47% (±7%; p < .0001); and TP3: 22% (±14%) versus 51% (±6%; p = .0178). For KMT2A-germline patients, 3-year EFS was: TP1: 88% (±12%) versus 87% (±5%; p = .73); TP2: 100% versus 88% (±5%; p = .24); and TP3: 100% versus 87% (±5%; p = .53). MRD was a strong independent outcome predictor in KMT2A-rearranged, but not KMT2A-germline infant ALL., (© 2023 Wiley Periodicals LLC.)

Hematologic malignancy is a risk factor for severe coronavirus disease 2019 (COVID-19) in adults; however, data specific to children with leukemia are limited. High-quality infectious adverse event data from the ongoing Children's Oncology Group (COG) standard-risk B acute lymphoblastic leukemia/lymphoma (ALL/LLy) trial, AALL1731, were analyzed to provide a disease-specific estimate of SARS-CoV-2 infection outcomes in pediatric ALL. Of 253 patients with reported infections, the majority (77.1%) were asymptomatic or mildly symptomatic (CTCAE grade 1/2) and there was a single COVID-19-related death. These data suggest SARS-CoV-2 infection does not confer substantial morbidity among young patients with B-lymphoblastic leukemia/lymphoma (B-ALL/LLy)., Competing Interests: The authors declare they have no conflicts of interest., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Previous studies have identified racial and ethnic disparities in childhood acute lymphocytic leukaemia survival. We aimed to establish whether disparities persist in contemporaneous cohorts and, if present, are attributable to differences in leukaemia biology or insurance status., Methods: Patients with newly diagnosed acute lymphocytic leukaemia in inpatient and outpatient centres in the USA, Canada, Australia, and New Zealand, aged 0-30 years, who had race or ethnicity data available, enrolled on eight completed Children's Oncology Group trials (NCT00103285, NCT00075725, NCT00408005, NCT01190930, NCT02883049, NCT02112916, NCT02828358, and NCT00557193) were included in this secondary analysis. Race and ethnicity were categorised as non-Hispanic White, Hispanic, non-Hispanic Black, non-Hispanic Asian, and non-Hispanic other. Event-free survival and overall survival were compared across race and ethnicity groups. The relative contribution of clinical and biological disease prognosticators and insurance status was examined through multivariable regression models, both among the entire cohort and among those with B-cell lineage versus T-cell lineage disease., Findings: Between Jan 1, 2004, and Dec 31, 2019, 24 979 eligible children, adolescents, and young adults with acute lymphocytic leukaemia were enrolled, of which 21 152 had race or ethnicity data available. 11 849 (56·0%) were male and 9303 (44·0%) were female. Non-Hispanic White patients comprised the largest racial or ethnic group (13 872 [65·6%]), followed by Hispanic patients (4354 [20·6%]), non-Hispanic Black patients (1517 [7·2%]), non-Hispanic Asian (n=1071 [5·1%]), and non-Hispanic other (n=338 [1·6%]). 5-year event-free survival was 87·4% (95% CI 86·7-88·0%) among non-Hispanic White patients compared with 82·8% (81·4-84·1%; hazard ratio [HR] 1·37, 95% CI 1·26-1·49; p<0·0001) among Hispanic patients and 81·8% (79·3-84·0; HR 1·45, 1·28-1·65; p<0·0001) among non-Hispanic Black patients. Non-hispanic Asian patients had a 5-year event-free survival of 88·1% (95% CI 85·5-90·3%) and non-Hispanic other patients had a survival of 82·8% (76·4-87·6%). Inferior event-free survival among Hispanic patients was substantially attenuated by disease prognosticators and insurance status (HR decreased from 1·37 [1·26-1·49; p<0·0001] to 1·11 [1·00-1·22; p=0·045]). The increased risk among non-Hispanic Black patients was minimally attenuated (HR 1·45 [1·28-1·65; p<0·0001] to 1·32 [1·14-1·52; p<0·0001]). 5-year overall survival was 93·6% (91·5-95·1%) in non-Hispanic Asian patients, 93·3% (92·8-93·7%) in non-Hispanic White patients, 89·9% (88·7-90·9%) in Hispanic, 89·7% (87·6-91·4%) in non-Hispanic Black patients, 88·9% (83·2-92·7%) in non-Hispanic other patients. Disparities in overall survival were wider than event-free survival (eg, among non-Hispanic other patients, the HR for event-free survival was 1·43 [1·10-1·85] compared with 1·74 [1·27-2·40] for overall survival). Disparities were restricted to patients with B-cell acute lymphocytic leukaemia, no differences in event-free survival or overall survival were seen in the T-cell acute lymphocytic leukaemia group., Interpretation: Substantial disparities in outcome for B-cell acute lymphocytic leukaemia persist by race and ethnicity, but are not observed in T-cell acute lymphocytic leukaemia. Future studies of relapsed patients, access to and quality of care, and other potential aspects of structural racism are warranted to inform interventions aimed at dismantling racial and ethnic disparities., Funding: National Cancer Institute and St Baldrick's Foundation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

As diseases like cancer are increasingly understood on a molecular level, clinical trials are being designed to reveal or validate subpopulations in which an experimental therapy has enhanced benefit. Such biomarker-driven designs, particularly "adaptive enrichment" designs that initially enroll an unselected population and then allow for later restriction of accrual to "marker-positive" patients based on interim results, are increasingly popular. Many biomarkers of interest are naturally continuous, however, and most existing design approaches either require upfront dichotomization or force monotonicity through algorithmic searches for a single marker threshold, thereby excluding the possibility that the continuous biomarker has a nondisjoint and truly nonlinear or nonmonotone prognostic relationship with outcome or predictive relationship with treatment effect. To address this, we propose a novel trial design that leverages both the actual shapes of any continuous marker effects (both prognostic and predictive) and their corresponding posterior uncertainty in an adaptive decision-making framework. At interim analyses, this marker knowledge is updated and overall or marker-driven decisions are reached such as continuing enrollment to the next interim analysis or terminating early for efficacy or futility. Using simulations and patient-level data from a multi-center Children's Oncology Group trial in Acute Lymphoblastic Leukemia, we derive the operating characteristics of our design and compare its performance to a traditional approach that identifies and applies a dichotomizing marker threshold., (© 2021 The International Biometric Society.)

Infections cause substantial morbidity for children with acute lymphoblastic leukemia (ALL). Therefore, accurate characterization of infectious adverse events (AEs) reported on clinical trials is imperative to defining, comparing, and managing safety and toxicity. Here, we describe key processes implemented to improve reporting of infectious AEs on two active phase III Children's Oncology Group (COG) ALL trials. Processes include: (a) identifying infections as a targeted toxicity, (b) incorporation of infection-specific case report form questions, and (c) physician review of AEs with real-time data cleaning. Preliminary assessment of these processes suggests improved reporting, as well as opportunities for further improvement., (© 2022 Wiley Periodicals LLC.)

Background: Children with B-acute lymphoblastic leukemia (B-ALL) are at risk for chemotherapy-induced peripheral neuropathy (CIPN). Children's Oncology Group AALL0932 randomized reduction in vincristine and dexamethasone (every 4 weeks vs 12 weeks during maintenance in the average-risk subset of National Cancer Institute standard-B-ALL (SR AR B-ALL). We longitudinally measured CIPN, overall and by treatment group., Methods: AALL0932 standard-B-ALL patients aged 3 years and older were evaluated at T1-T4 (end consolidation, maintenance month 1, maintenance month 18, 12 months posttherapy). Physical and occupational therapists (PT/OT) measured motor CIPN (hand and ankle strength, dorsiflexion and plantarflexion range of motion), sensory CIPN (finger and toe vibration and touch), function (dexterity [Purdue Pegboard], and walking efficiency [Six-Minute Walk]). Proxy-reported function (Pediatric Outcome Data Collection Instrument) and quality of life (Pediatric Quality of Life Inventory) were assessed. Age- and sex-matched z scores and proportion impaired were measured longitudinally and compared between groups., Results: Consent and data were obtained from 150 participants (mean age = 5.1 years [SD = 1.7], 48.7% female). Among participants with completed evaluations, 81.8% had CIPN at T1 (74.5% motor, 34.1% sensory). When examining severity of PT/OT outcomes, only handgrip strength (P < .001) and walking efficiency (P = .02) improved from T1-T4, and only dorsiflexion range of motion (46.7% vs 14.7%; P = .008) and handgrip strength (22.2% vs 37.1%; P = .03) differed in vincristine and dexamethasone every 4 weeks vs vincristine and dexamethasone 12 weeks at T4. Proxy-reported outcomes improved from T1 to T4 (P < .001), and most did not differ between groups., Conclusions: CIPN is prevalent early in B-ALL therapy and persists at least 12 months posttherapy. Most outcomes did not differ between treatment groups despite reduction in vincristine frequency. Children with B-ALL should be monitored for CIPN, even with reduced vincristine frequency., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: AALL0932 evaluated two randomized maintenance interventions to optimize disease-free survival (DFS) while reducing the burden of therapy in children with newly diagnosed NCI standard-risk (SR) B-acute lymphoblastic leukemia (B-ALL)., Methods: AALL0932 enrolled 9,229 patients with B-ALL; 2,364 average-risk (AR) patients were randomly assigned (2 × 2 factorial design) at the start of maintenance therapy to vincristine/dexamethasone pulses every 4 (VCR/DEX4) or every 12 (VCR/DEX12) weeks, and a starting dose of weekly oral methotrexate of 20 mg/m 2 (MTX20) or 40 mg/m 2 (MTX40)., Results: Five-year event-free survival and overall survival (OS) from enrollment (with 95% CIs), for all eligible and evaluable SR B-ALL patients (n = 9,226), were 92.0% (91.1% and 92.8%) and 96.8% (96.2% and 97.3%), respectively. The 5-year DFS and OS from the start of maintenance for randomly assigned AR patients were 94.6% (93.3% and 95.9%) and 98.5% (97.7% and 99.2%), respectively. The 5-year DFS and OS for patients randomly assigned to receive VCR/DEX4 (n = 1,186) versus VCR/DEX12 (n = 1,178) were 94.1% (92.2% and 96.0%) and 98.3% (97.2% and 99.4%) v 95.1% (93.3% and 96.9%) and 98.6% (97.7% and 99.6%), respectively ( P = .86 and .69). The 5-year DFS and OS for AR patients randomly assigned to receive MTX20 versus MTX40 were 95.1% (93.3% and 96.8%) and 98.8% (97.9% and 99.7%) v 94.2% (92.2% and 96.1%) and 98.1% (97.0% and 99.2%), respectively ( P = .92 and .89)., Conclusions: The 0NCI-SR AR B-ALL who received VCR/DEX12 had outstanding outcomes despite receiving one third of the vincristine/dexamethasone pulses previously used as standard of care on Children's Oncology Group (COG) trials. The higher starting dose of MTX of 40 mg/m 2 /week did not improve outcomes when compared with 20 mg/m 2 /week. The decreased frequency of vincristine/dexamethasone pulses has been incorporated into frontline COG B-ALL trials to decrease the burden of therapy for patients and their families., Competing Interests: Anne L. AngiolilloHonoraria: Servier PharmaceuticalsTravel, Accommodations, Expenses: Servier Pharmaceuticals Reuven J. SchoreResearch Funding: Janssen Research & Development, Amgen John A. KairallaStock and Other Ownership Interests: Johnson & Johnson Meenakshi DevidasHonoraria: PSI, Novartis Patrick Zweidler-McKayStock and Other Ownership Interests: Immunogen Michael J. BorowitzConsulting or Advisory Role: AmgenResearch Funding: Becton DickinsonTravel, Accommodations, Expenses: Beckman Coulter Brent WoodHonoraria: Amgen, Seattle Genetics, Abbvie, Janssen, Astellas PharmaConsulting or Advisory Role: SysmexResearch Funding: Amgen, Seattle Genetics, Pfizer, Juno Therapeutics, BiolineRx, Biosight, Stemline Therapeutics, Janssen Oncology, NovartisTravel, Accommodations, Expenses: Amgen Mary V. RellingResearch Funding: Servier Pharmaceutical Elizabeth A. RaetzResearch Funding: PfizerOther Relationship: Celgene Mignon L. LohConsulting or Advisory Role: MediSix Therapeutics Stephen P. HungerStock and Other Ownership Interests: Amgen, MerckHonoraria: AmgenConsulting or Advisory Role: NovartisNo other potential conflicts of interest were reported.

Infants with KMT2A-rearranged acute lymphoblastic leukemia (KMT2A-r ALL) have a poor prognosis. KMT2A-r ALL overexpresses FLT3, and the FLT3 inhibitor (FLT3i) lestaurtinib potentiates chemotherapy-induced cytotoxicity in preclinical models. Children's Oncology Group (COG) AALL0631 tested whether adding lestaurtinib to post-induction chemotherapy improved event-free survival (EFS). After chemotherapy induction, KMT2A-r infants received either chemotherapy only or chemotherapy plus lestaurtinib. Correlative assays included FLT3i plasma pharmacodynamics (PD), which categorized patients as inhibited or uninhibited, and FLT3i ex vivo sensitivity (EVS), which categorized leukemic blasts as sensitive or resistant. There was no difference in 3-year EFS between patients treated with chemotherapy plus lestaurtinib (n = 67, 36 ± 6%) vs. chemotherapy only (n = 54, 39 ± 7%, p = 0.67). However, for the lestaurtinib-treated patients, FLT3i PD and FLT3i EVS significantly correlated with EFS. For FLT3i PD, EFS for inhibited/uninhibited was 59 ± 10%/28 ± 7% (p = 0.009) and for FLTi EVS, EFS for sensitive/resistant was 52 ± 8%/5 ± 5% (p < 0.001). Seventeen patients were both inhibited and sensitive, with an EFS of 88 ± 8%. Adding lestaurtinib did not improve EFS overall, but patients achieving potent FLT3 inhibition and those whose leukemia blasts were sensitive FLT3-inhibition ex vivo did benefit from the addition of lestaurtinib. Patient selection and PD-guided dose escalation may enhance the efficacy of FLT3 inhibition for KMT2A-r infant ALL.

Purpose: To characterize academic and adaptive skill outcomes in survivors of high-risk B-lineage acute lymphoblastic leukemia (HR B-ALL)., Methods: Participants were 178 patients enrolled on a nontherapeutic clinical trial that aimed to characterize neurocognitive and functional outcomes (ie, academic achievement and adaptive skills) following treatment for childhood HR B-ALL. Eligible patients were treated on Children's Oncology Group AALL0232 clinical trial that included two treatment randomizations: methotrexate delivery (high or escalating dose) and corticosteroid (dexamethasone or prednisone). Academic achievement and adaptive skills were evaluated at one time point, 8-24 months after completing treatment., Results: Multivariable logistic regression showed no significant association between treatment variables and outcomes after accounting for age at diagnosis, sex, and insurance status. In multivariable analyses accounting for sex and insurance status, survivors <10 years old at diagnosis had significantly lower scores in Math (P = .02). In multivariable analyses accounting for sex and age at diagnosis, scores for children with US public health insurance were significantly lower than those with US private or military insurance across all academic and adaptive skills (all P-values ≤.04). Results from univariate analyses showed that boys had significantly lower scores than girls across all adaptive skill domains (all P-values ≤.04)., Conclusion: Regardless of treatment randomization, survivors of HR B-ALL <10 years at diagnosis are at risk for deficits in Math and overall adaptive functioning; overall adaptive skills for boys were significantly poorer. Screening and early intervention for patients at highest risk, particularly young patients and lower resourced families, should be prioritized., (© 2021 Wiley Periodicals LLC.)

In personalized medicine, it is often desired to determine if all patients or only a subset of them benefit from a treatment. We consider estimation in two-stage adaptive designs that in stage 1 recruit patients from the full population. In stage 2, patient recruitment is restricted to the part of the population, which, based on stage 1 data, benefits from the experimental treatment. Existing estimators, which adjust for using stage 1 data for selecting the part of the population from which stage 2 patients are recruited, as well as for the confirmatory analysis after stage 2, do not consider time to event patient outcomes. In this work, for time to event data, we have derived a new asymptotically unbiased estimator for the log hazard ratio and a new interval estimator with good coverage probabilities and probabilities that the upper bounds are below the true values. The estimators are appropriate for several selection rules that are based on a single or multiple biomarkers, which can be categorical or continuous., (© 2020 The Authors. Statistics in Medicine published by John Wiley & Sons, Ltd.)

Purpose: The high-risk stratum of Children's Oncology Group Study AALL1131 was designed to test the hypothesis that postinduction CNS prophylaxis with intrathecal triple therapy (ITT) including methotrexate, hydrocortisone, and cytarabine would improve the postinduction 5-year disease-free survival (DFS) compared with intrathecal methotrexate (IT MTX), when given on a modified augmented Berlin-Frankfurt-Münster backbone., Patients and Methods: Children with newly diagnosed National Cancer Institute (NCI) high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) or NCI standard-risk B-ALL with defined minimal residual disease thresholds during induction were randomly assigned to receive postinduction IT MTX or ITT. Patients with CNS3-status disease were not eligible. Postinduction IT therapy was given for a total of 21 to 26 doses. Neurocognitive assessments were performed during therapy and during 1 year off therapy., Results: Random assignment was closed to accrual in March 2018 after a futility boundary had been crossed, concluding that ITT could not be shown to be superior to IT MTX. The 5-year postinduction DFS and overall survival rates (± SE) of children randomly assigned to IT MTX versus ITT were 93.2% ± 2.1% v 90.6% ± 2.3% ( P = .85), and 96.3% ± 1.5% v 96.7% ± 1.4% ( P = .77), respectively. There were no differences in the cumulative incidence of isolated bone marrow relapse, isolated CNS relapse, or combined bone marrow and CNS relapse rates, or in toxicities observed for patients receiving IT MTX compared with ITT. There were no significant differences in neurocognitive outcomes for patients receiving IT MTX compared with ITT., Conclusion: Postinduction CNS prophylaxis with ITT did not improve 5-year DFS for children with HR B-ALL. The standard of care for CNS prophylaxis for children with B-ALL and no overt CNS involvement remains IT MTX.

In the United States, cancer remains the leading cause of disease-related death in children. Although survival from any pediatric cancer has improved dramatically during past decades, a number of cancers continue to yield dismal prognoses, which has motivated the continued study of novel therapeutic strategies. Furthermore, even patients cured of pediatric cancer often experience severe adverse effects of treatment and other long-term health implications, such as cardiotoxicity or loss of fertility. For these patients, improved risk stratification to identify those who could safely receive alternate or less-intensive therapy without affecting prognosis is a key objective. Fortunately, pediatric cancers are rare overall, but even among patients with the same narrow cancer type, there is often broad heterogeneity in terms of prognosis, molecular features or pathology, current treatment strategies, and scientific objectives. As a result, the design of clinical trials in the pediatric cancer setting is challenged by a number of practical issues that must be addressed to ensure trial feasibility for this vulnerable group of patients. In this review, we discuss some of the unique trial design considerations often encountered in any rare tumor setting through the lens of our experiences as faculty statisticians for the Children's Oncology Group, the largest organization in the world dedicated exclusively to pediatric cancer research and clinical trials. These topics include risk stratification within individual trials, relaxation of trial operating characteristics and parameters, use of historical controls, and address of noninferiority-type objectives in small cohorts. We review each in terms of practical motivation, present challenges, and potential solutions described in the literature and implemented in selected example trials from the Children's Oncology Group., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Arzu Onar-ThomasHonoraria: Eli Lilly Research Funding: Novartis (Inst), Apexigen (Inst), Pfizer (Inst), Celgene (Inst), Merck (Inst) Travel, Accommodations, Expenses: Eli LillyJohn A. KairallaStock and Other Ownership Interests: Johnson & Johnson, Sophiris Bio No other potential conflicts of interest were reported., (© 2019 by American Society of Clinical Oncology.)

Background: We provide the first examination of mitochondrial DNA (mtDNA) variants and pulmonary function in older persons., Methods: Cross-sectional associations between mtDNA variants and pulmonary function were evaluated as a combined p-values meta-analysis, using data from two independent cohorts of older persons. The latter included white and black participants, aged ≥70 years, from the Lifestyle Interventions and Independence for Elders study (LIFE) (N = 1247) and the Health, Aging and Body Composition study (Health ABC) (N = 731), respectively. Pulmonary function included the forced expiratory volume in one-second as a Z-score (FEV1z) and the maximal inspiratory pressure (MIP) in cm of water., Results: In black participants, significant associations were found between mtDNA variants and MIP: m.7146A > G, COI (p = 3E-5); m.7389 T > C, COI (p = 2E-4); m.15301G > A, CYB (p = 9E-5); m.16265A > G, HV1 (p = 9E-5); meta-analytical p-values <0.0002. Importantly, these mtDNA variants were unique to black participants and were not present in white participants. Moreover, in black participants, aggregate genetic effects on MIP were observed across mutations in oxidative phosphorylation complex IV (p = 0.004), complex V (p = 0.0007), and hypervariable (p = 0.003) regions. The individual and aggregate variant results were significant after adjustment for multiple comparisons. Otherwise, no significant associations were detected for MIP in whites or for FEV1z in whites or blacks., Conclusions: We have shown that mtDNA variants of African origin are cross-sectionally associated with MIP, a measure of respiratory muscle strength. Thus, our results establish the rationale for longitudinal studies to evaluate whether mtDNA variants of African origin identify those at risk of subsequently developing a respiratory muscle impairment (lower MIP values)., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: The aims of the study were (a) to provide knowledge about the provision of assistive devices in practice and (b) to describe the challenges of standardizing device provision., Design: This is a retrospective study using Department of Veteran Affairs National Prosthetic Patient Database and other administrative databases. The cohort included all veterans treated by the Veterans Health Administration for stroke during fiscal years 2007-2008. Descriptive methods were used to analyze data with emphasis on inspecting relationships between device provision and motor and cognitive function using Functional Independence Measure scores., Results: A total of 8374 veterans treated for stroke and receiving at least one assistive device are included. Individuals who received standard or caregiver controlled wheelchairs tended to be older, and those who received ultralight or caregiver controlled wheelchairs had a higher proportion of Hispanics than the overall cohort. Veterans who received any type of wheelchair had lower motor, cognitive, and total functioning scores than the cohort as a whole. Veterans who received canes had the highest functioning. Veteran patients who received patient lifts and beds had lower cognitive scores compared with the overall cohort., Conclusions: Functional status can provide some objectivity to the largely subjective assistive device provision decision-making process; however, many other factors must be considered simultaneously, complicating efforts to standardize provision.

Declines in walking speed are associated with a variety of poor health outcomes including disability, comorbidity, and mortality. While genetic factors are putative contributors to variability in walking, few genetic loci have been identified for this trait. We examined the role of mitochondrial genomic variation on walking speed by sequencing the entire mitochondrial DNA (mtDNA). Data were meta-analyzed from 1758 Lifestyle Interventions and Independence for Elders (LIFE) Study and replication data from 730 Health, Aging, and Body Composition (HABC) Study participants with baseline walking speed information. Participants were 69+ years old of diverse racial backgrounds (African, European, and other race/ethnic groups) and had a wide range of mean walking speeds [4-6 m (0.78-1.09 m/s) and 400 m (0.83-1.24 m/s)]. Meta-analysis across studies and racial groups showed that m.12705C>T, ND5 variant was significantly associated (p < 0.0001) with walking speed at both short and long distances. Replication and meta-analysis also identified statistically significant walking speed associations (p < 0.0001) between the m.5460.G>A, ND2 and m.309C>CT, HV2 variants at short and long distances, respectively. All results remained statistically significant after multiple comparisons adjustment for 499 mtDNA variants. The m.12705C>T variant can be traced to the beginnings of human global migration and that cells carrying this variant display altered tRNA expression. Significant pooled effects related to stopping during the long-distance walk test were observed across OXPHOS complexes I (p = 0.0017) and III (p = 0.0048). These results suggest that mtDNA-encoded variants are associated with differences in walking speed among older adults, potentially identifying those at risk of developing mobility impairments.

Background Age-related changes in blood pressure are associated with a variety of poor health outcomes. Genetic factors are proposed contributors to age-related increases in blood pressure, but few genetic loci have been identified. We examined the role of mitochondrial genomic variation in blood pressure by sequencing the mitochondrial genome. Methods and Results Mitochondrial DNA (mt DNA ) data from 1755 participants from the LIFE (Lifestyle Interventions and Independence for Elders) studies and 788 participants from the Health ABC (Health, Aging, and Body Composition) study were evaluated using replication analysis followed by meta-analysis. Participants were aged ≥69 years, of diverse racial backgrounds, and assessed for systolic blood pressure ( SBP ), diastolic blood pressure, and mean arterial pressure. After meta-analysis across the LIFE and Health ABC studies, statistically significant associations of mt DNA variants with higher SBP (m.3197T>C, 16S rRNA ; P=0.0005) and mean arterial pressure (m.15924A>G, t-RNA-thr; P=0.004) were identified in white participants. Among black participants, statistically significant associations with higher SBP (m.93A>G, HVII ; m.16183A>C, HVI ; both P=0.0001) and mean arterial pressure (m.16172T>C, HVI ; m.16183A>C, HVI ; m.16189T>C, HVI ; m.12705C>T; all P's<0.0004) were observed. Significant pooled effects on SBP were observed across all transfer RNA regions ( P=0.0056) in white participants. The individual and aggregate variant results are statistically significant after multiple comparisons adjustment for the number of mt DNA variants and mitochondrial regions examined. Conclusions These results suggest that mt DNA -encoded variants are associated with variation in SBP and mean arterial pressure among older adults. These results may help identify mitochondrial activities to explain differences in blood pressure in older adults and generate new hypotheses surrounding mt DNA variation and the regulation of blood pressure. Clinical Trial Registration URL : http://www.ClinicalTrials.gov . Unique identifiers: NCT 01072500 and NCT 00116194.

Purpose Addition of imatinib to intensive chemotherapy improved survival for children and young adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Compared with imatinib, dasatinib has increased potency, CNS penetration, and activity against imatinib-resistant clones. Patients and Methods Children's Oncology Group (COG) trial AALL0622 (Bristol Myers Squibb trial CA180-204) tested safety and feasibility of adding dasatinib to intensive chemotherapy starting at induction day 15 in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia age 1 to 30 years. Allogeneic hematopoietic stem-cell transplantation (HSCT) was recommended for patients at high risk based on slow response and for those with a matched family donor regardless of response after at least 11 weeks of therapy. Patients at standard risk based on rapid response received chemotherapy plus dasatinib for an additional 120 weeks. Patients with overt CNS leukemia received cranial irradiation. Results Sixty eligible patients were enrolled. Five-year overall (OS) and event-free survival rates (± standard deviations [SD]) were 86% ± 5% and 60% ± 7% overall, 87% ± 5% and 61% ± 7% for standard-risk patients (n = 48; 19% underwent HSCT), and 89% ± 13% and 67% ± 19% for high-risk patients (n = 9; 89% underwent HSCT), respectively. Five-year cumulative incidence (± SD) of CNS relapse was 15% ± 6%. Outcomes (± SDs) were similar to those in COG AALL0031, which used the same chemotherapy with continuous imatinib: 5-year OS of 81% ± 6% versus 86% ± 5% ( P = .63) and 5-year disease-free survival of 68% ± 7% versus 60% ± 7% ( P = 0.31) for AALL0031 versus AALL0622, respectively. IKZF1 deletions, present in 56% of tested patients, were associated with significantly inferior OS and event-free survival overall and in standard-risk patients. Conclusion Dasatinib was well tolerated with chemotherapy and provided outcomes similar to those with imatinib in COG AALL0031, where all patients received cranial irradiation. Our results support limiting HSCT to slow responders and suggest a potential role for transplantation in rapid responders with IKZF1 deletions.

ABSTRACTBackground:Behavioral and psychological symptoms of dementia (BPSD) are a primary manifestation of brain dysfunction in dementia and a great challenge in caregiving. While BPSD are historically associated with caregiver distress, it is unclear whether there is an identifiable point where BPSD number is associated with heightened caregiver distress. The purpose of this study was to determine if such a tipping point exists to assist clinicians in identifying caregiver compromise., Methods: Analyses were performed with three datasets totaling 569 community-dwelling persons with dementia and their caregivers. Each included identical demographic, BPSD, cognitive, and caregiver well-being measures. Linear regression was performed with 16 BPSD symptoms on caregiver well-being measures and predictive values determined with receiver operating characteristic (ROC) curves and pre-defined scores for clinically significant distress., Results: Of the 569 persons with dementia, 549 (96%) displayed at least one BPSD, mean of 5.7 (SD = 3.06) symptoms in the past month. After controlling for covariates, BPSD symptom number was significantly associated with caregiver depression and burden (p < 0.01 for both models). Findings indicate ≥ 4 BPSD has strong predictive values for depression (sensitivity 85%, specificity 44%, area under ROC curve 0.62, p < 0.01), and burden (sensitivity 84%, specificity 43%, area under ROC curve 0.67, p < 0.01)., Conclusions: Caring for persons with four or more BPSD appears to reflect a tipping point for clinically meaningful distress. Findings have implications for clinicians working with persons with dementia and their caregivers and suggest need for continuous monitoring of BPSD and identification of at risk caregivers.

Purpose Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for neurocognitive deficits that are associated with treatment, individual, and environmental factors. This study examined the impact of different methotrexate (MTX) and corticosteroid treatment strategies on neurocognitive functioning in children with high-risk B-lineage ALL. Methods Participants were randomly assigned to receive high-dose MTX with leucovorin rescue or escalating dose MTX with PEG asparaginase without leucovorin rescue. Patients were also randomly assigned to corticosteroid therapy that included either dexamethasone or prednisone. A neurocognitive evaluation of intellectual functioning (IQ), working memory, and processing speed (PS) was conducted 8 to 24 months after treatment completion (n = 192). Results The method of MTX delivery and corticosteroid assignment were unrelated to differences in neurocognitive outcomes after controlling for ethnicity, race, age, gender, insurance status, and time off treatment; however, survivors who were age < 10 years at diagnosis (n = 89) had significantly lower estimated IQ ( P < .001) and PS scores ( P = .02) compared with participants age ≥ 10 years. In addition, participants who were covered by US public health insurance had estimated IQs that were significantly lower ( P < .001) than those with US private or military insurance. Conclusion Children with high-risk B-lineage ALL who were age < 10 years at diagnosis are at risk for deficits in IQ and PS in the absence of cranial radiation, regardless of MTX delivery or corticosteroid type. These data may serve as a basis for developing screening protocols to identify children who are at high risk for deficits so that early intervention can be initiated to mitigate the impact of therapy on neurocognitive outcomes.

Background: Age-associated decline in central cholinergic activity makes older adults susceptible to the harmful effects of anticholinergic (AC) medications; however, there is an inadequate understanding of the association and possible effects of AC drugs on cognition. This cross-sectional study examines the associations of AC medications on cognition among older adults with questionable cognitive impairment (QCI)., Methods: For this cross-sectional study, we used a multicenter database of community-dwelling older adults (N = 7351) aged 60+ years with QCI, from September 2005 to March 2014, as the baseline data. The Anticholinergic Drug Scale was used to categorize AC drug load into no, low, or moderate/high groups. Individuals with a Clinical Dementia Rating-Sum of Boxes score between 0.5 and 2.5 were identified as having QCI, while cognitive performance was evaluated using the Neuropsychological Test Battery. The mean z-scores of neuropsychological tests were grouped into a global cognition score., Results: Participants who took AC medications were older, largely female, and had a higher prevalence of incontinence than those without AC exposure. Global cognition was significantly greater in the moderate/high-AC group than the no-AC group (-0.23 ± 0.53 vs. -0.32 ± 0.53). Multivariable linear regression showed that the global cognition score among the low- and moderate/high-AC groups, compared with the no-AC group, was 0.064 higher (p = 0.006 and p = 0.12, respectively)., Conclusions: This cross-sectional study indicates that older adults with QCI who were exposed to AC medications might have higher global cognitive scores than those without AC exposure. The observed associations indicate that older adults might experience some beneficial cognitive effects from AC drugs, possibly due to the therapeutic effects of these medications in controlling comorbidities, thus outweighing their adverse effects on cognition.

Objective: The objective of this study was to determine whether facility-level, structural factors affect the provision of assistive devices and services., Design: A retrospective design was used. Activities of daily living and mobility-related devices were categorized into 11 types. Logistic regression models were performed for each type of device, controlling for patient-level and facility-level covariates., Results: Non-veteran-level factors significantly affect the provision of assistive devices, even after covariate adjustment. Increased rehabilitation clinician staffing by 1 full-time equivalent position was associated with increased provision odds of 1%-5% for 5 of 11 types of devices. Lower facility complexity was significantly associated with increased provision odds of 35%-59% for 3 types of devices and with decreased provision odds of 16%-69% for 3 types of devices., Conclusion: System-level factors, in addition to patient need, significantly affect the provision of assistive devices. Provision guidelines could assist clinicians in making decisions about device provision., (Copyright © 2016 by the American Occupational Therapy Association, Inc.)

Context: Medical and health policy decision makers require improved design and analysis methods for comparative effectiveness research (CER) trials. In CER trials, there may be limited information to guide initial design choices. In general settings, adaptive designs (ADs) have effectively overcome limits on initial information. However, CER trials have fundamental differences from standard clinical trials including population heterogeneity and a vaguer concept of a "minimum clinically meaningful difference"., Objective: To explore the use of a particular form of ADs for comparing treatments within the CER trial context., Methods: We review the current state of clinical CER, identify areas of CER as particularly strong candidates for application of novel ADs, and illustrate potential usefulness of the designs and methods for two group comparisons., Results: ADs can stabilize power. The designs ensure adequate power for true effects are at least at clinically significant preplanned effect size, or when variability is larger than expected. The designs allow for sample size savings when the true effect is larger or when variability is smaller than planned., Conclusion: ADs in CER have great potential to allow trials to successfully and efficiently make important comparisons.

Idiopathic nephrotic syndrome (INS) includes three different entities: minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and mesangial proliferative glomerulonephritis. Historically, this condition has been attributed to a T-cell disorder resulting in the secretion of a circulating factor that increases glomerular permeability to plasma proteins. The therapeutic approach to control the proteinuria of INS remains the use of drugs that have been considered to suppress the production of the "circulating factor" secreted by T cells. Recently, rituximab (RTX), a chimeric monoclonal antibody directed against the CD20 cell surface receptor expressed on B cells, has emerged as potential therapeutic agent. The number of publications reporting clinical experience with RTX in the treatment of nephrotic syndrome has greatly increased in the last few years. However, there is currently no good evidence from clinical or experimental studies that support a role of RTX in the treatment of MCD and FSGS proteinuria. In summary, there is the need for a better understanding of the pathogenesis of the proteinuria in INS and the potential role of RTX in this condition.

The high prevalence of health conditions among U.S. women receiving Temporary Assistance for Needy Families (TANF, or 'welfare') impedes the ability of many in this group to move from 'welfare-to-work', and the economic recession has likely exacerbated this problem. Despite this, few interventions have been developed to improve employment outcomes by addressing the health needs of women receiving TANF, and little is known about the impact of economic downturns on the employment trajectory of this group. Using data from a recent randomized controlled trial (RCT) that tested the efficacy of a public health nursing (PHN) intervention to address the chronic health condition needs of 432 American women receiving TANF, we examine the effect of the intervention and of recession exposure on employment. We further explore whether intervention effects were modified by select sociodemographic and health characteristics. Both marginal and more robust intervention effects were noted for employment-entry outcomes (any employment, p = 0.05 and time-to-employment, p = 0.01). There were significant effects for recession exposure on employment-entry (any employment, p = 0.002 and time-to-employment, p < 0.001). Neither the intervention nor recession exposure influenced longer-term employment outcomes (employment rate or maximum continuous employment). Intervention effects were not modified by age, education, prior TANF receipt, functional status, or recession exposure, suggesting the intervention was equally effective in improving employment-entry across a fairly heterogeneous group both before and after the recession onset. These findings advance our understanding of the health and employment dynamics among this group of disadvantaged women under variable macroeconomic conditions, and have implications for guiding health and TANF-related policy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

To assess the association between perinatal care expenditures and a Medicaid waiver to increase Florida Healthy Start services among Florida Medicaid non-managed care organization (non-MCO) program enrollees. We assessed perinatal care expenditures from Medicaid claims and encounter data among non-MCO enrollees with increased risk pregnancies who gave birth in Florida during 1998-2006. We used a pre-post design to compare adjusted perinatal medical expenditures among women who received Healthy Start care coordination (n = 41,067) to women who were not contacted by the Healthy Start program after screening (n = 24,282). We calculated adjusted average costs and difference-in-differences using marginal estimates from multivariable linear mixed regression models. From the pre-waiver (January 1998-July 2001) to the late-post waiver (July 2004-December 2006), all prenatal medical costs increased $274 among care coordination participants and decreased $601 among women not contacted by the Healthy Start program, equaling a $875 increased cost difference between care coordination and no contact groups. During this same time period, delivery related expenditures increased $395 less among care coordination participants compared to women not contacted by Healthy Start. Additionally, infant medical care costs during days 29-365 decreased by an average of $240 less among the care coordination compared to the no contact group. The Medicaid waiver may have decreased delivery costs, but medical costs were increased following the waiver when considering all perinatal care. Further exploration of factors associated with the decreased delivery costs may help develop more efficient prenatal support programs.

Unlabelled: We hypothesized that, in patients with vesicoureteral reflux (VUR) grade IV or V, hydronephrosis will likely be found, if the patient has a full bladder during the renal ultrasound examination. Eight hundred thirty-seven patients were included in the study. Patients ranged in age from <1 month to 18.7 years, with a median age of 1.3 years. Five hundred sixty-nine were female and 268 were male. In this retrospective study, each patient underwent a voiding cystourethrogram (VCUG) and a renal ultrasound examination. The presence of hydronephrosis and bladder filling status in 131 renal units with VUR grade IV or V was evaluated. Sensitivity and specificity for hydronephrosis to detect the presence of VUR grades IV and V were 60 and 92 %, respectively. Positive predictive value and negative predictive value were 74 and 87 %, respectively. Odds ratios for the relationship between hydronephrosis and severe VUR was significant (p = 0.046)., Conclusion: In patients with grade IV or V VUR, hydronephrosis will be observed in the presence of a full bladder. Therefore, a renal ultrasound could be considered a screening test to decide on performing a VCUG.

Adaptive designs allow planned modifications based on data accumulating within a study. The promise of greater flexibility and efficiency stimulates increasing interest in adaptive designs from clinical, academic, and regulatory parties. When adaptive designs are used properly, efficiencies can include a smaller sample size, a more efficient treatment development process, and an increased chance of correctly answering the clinical question of interest. However, improper adaptations can lead to biased studies. A broad definition of adaptive designs allows for countless variations, which creates confusion as to the statistical validity and practical feasibility of many designs. Determining properties of a particular adaptive design requires careful consideration of the scientific context and statistical assumptions. We first review several adaptive designs that garner the most current interest. We focus on the design principles and research issues that lead to particular designs being appealing or unappealing in particular applications. We separately discuss exploratory and confirmatory stage designs in order to account for the differences in regulatory concerns. We include adaptive seamless designs, which combine stages in a unified approach. We also highlight a number of applied areas, such as comparative effectiveness research, that would benefit from the use of adaptive designs. Finally, we describe a number of current barriers and provide initial suggestions for overcoming them in order to promote wider use of appropriate adaptive designs. Given the breadth of the coverage all mathematical and most implementation details are omitted for the sake of brevity. However, the interested reader will find that we provide current references to focused reviews and original theoretical sources which lead to details of the current state of the art in theory and practice.

Pain can have a throbbing quality, especially when it is severe and disabling. It is widely held that this throbbing quality is a primary sensation of one's own arterial pulsations, arising directly from the activation of localized pain-sensory neurons by closely apposed blood vessels. We examined this presumption more closely by simultaneously recording the subjective report of the throbbing rhythm and the arterial pulse in human subjects of either sex with throbbing dental pain-a prevalent condition whose pulsatile quality is widely regarded a primary sensation. Contrary to the generally accepted view, which would predict a direct correspondence between the two, we found that the throbbing rate (44 bpm ± 3 SEM) was much slower than the arterial pulsation rate (73 bpm ± 2 SEM, p < 0.001), and that the two rhythms exhibited no underlying synchrony. Moreover, the beat-to-beat variation in arterial and throbbing events observed distinct fractal properties, indicating that the physiological mechanisms underlying these rhythmic events are distinct. Confirmation of the generality of this observation in other pain conditions would support an alternative hypothesis that the throbbing quality is not a primary sensation but rather an emergent property, or perception, whose "pacemaker" lies within the CNS. Future studies leading to an improved understanding of the neurobiological basis of clinically relevant pain qualities, such as throbbing, will also enhance our ability to measure and therapeutically target severe and disabling pain.

This study sought to determine if a parsimonious pressure ulcer (PU) predictive model could be identified specific to acute care to enhance the current PU risk assessment tool (Braden Scale) utilized within veteran facilities. Factors investigated include: diagnosis of gangrene, anemia, diabetes, malnutrition, osteomyelitis, pneumonia/pneumonitis, septicemia, candidiasis, bacterial skin infection, device/implant/graft complications, urinary tract infection, paralysis, senility, respiratory failure, acute renal failure, cerebrovascular accident, or congestive heart failure during hospitalization; patient's age, race, smoking status, history of previous PU, surgery, hours in surgery; length of hospitalization, and intensive care unit days. Retrospective chart review and logistic regression analyses were used to examine Braden scores and other risk factors in 213 acutely ill veterans in North Florida with (n = 100) and without (n = 113) incident PU from January-July 2008. Findings indicate four medical factors (malnutrition, pneumonia/pneumonitis, candidiasis, and surgery) have stronger predictive value (sensitivity 83%, specificity 72%, area under receiver operating characteristic [ROC] curve 0.82) for predicting PUs in acutely ill veterans than Braden Scale total scores alone (sensitivity 65%, specificity 70%, area under ROC curve 0.70). In addition, accounting for four medical factors plus two Braden subscores (activity and friction) demonstrates better overall model performance (sensitivity 80%, specificity 76%, area under ROC curve 0.88)., (© 2012 by the Wound Healing Society.)

Parents of children with autism report high rates of stress. Parental differences in stress are inconsistent, with most research indicating that mothers report higher levels of stress than fathers. We explored parental differences before and after an in-home training program. Fathers were taught an intervention designed to improve their child's social reciprocity and communication; they then trained mothers. Stress was assessed with the Parenting Stress Index-Short Form, and family dynamics was assessed with the Family Adaptability and Cohesion Evaluation Scales II. Both mothers and fathers reported high preintervention levels of stress. After intervention, fathers' stress was reduced, but not significantly, possibly because of the variability in fathers' scores; mothers' stress scores were significantly reduced. Parenting styles were significantly different before and after intervention. Interdisciplinary teams, including occupational therapists, nurses, and special educators, can work.together to have a positive impact on the lives of families of children with autism.

Objectives: We evaluated the effectiveness of a community-based participatory research-grounded intervention among women receiving Temporary Assistance for Needy Families (TANF) with chronic health conditions in increasing (1) health care visits, (2) Medicaid knowledge and skills, and (3) health and functional status., Methods: We used a randomized controlled trial design to assign 432 women to a public health nurse case management plus Medicaid intervention or a wait-control group. We assessed Medicaid outcomes pre- and posttraining; other outcomes were assessed at 3, 6, and 9 months., Results: Medicaid knowledge and skills improved (P < .001 for both). Intervention group participants were more likely to have a new mental health visit (odds ratio [OR] = 1.92; P = .007), and this likelihood increased in higher-risk subgroups (OR = 2.03 and 2.83; P = .04 and .006, respectively). Depression and functional status improved in the intervention group over time (P = .016 for both). No differences were found in routine or preventive care, or general health., Conclusions: Health outcomes among women receiving TANF can be improved with public health interventions. Additional strategies are needed to further reduce health disparities in this population.

An internal pilot with interim analysis (IPIA) design combines interim power analysis (an internal pilot) with interim data analysis (two stage group sequential). We provide IPIA methods for single df hypotheses within the Gaussian general linear model, including one and two group t tests. The design allows early stopping for efficacy and futility while also re-estimating sample size based on an interim variance estimate. Study planning in small samples requires the exact and computable forms reported here. The formulation gives fast and accurate calculations of power, type I error rate, and expected sample size.