Search

Objective: Examine the influence of household income on health‐related quality of life (HRQOL) among children with newly diagnosed acute myeloid leukemia (AML). Design: Secondary analysis of data prospectively collected from pediatric patients receiving treatment for AML at 14 hospitals across the United States. Exposure: Household income was self‐reported on a demographic survey. The examined mediators included the acuity of presentation and treatment toxicity. Outcome: Caregiver proxy reported assessment of patient HRQOL from the Peds QL 4.0 survey. Result: Children with AML (n = 131) and caregivers were prospectively enrolled to complete PedsQL assessments. HRQOL scores were better for patients in the lowest versus highest income category (mean ± SD: 76.0 ± 14 household income <$25,000 vs. 59.9 ± 17 income ≥$75,000; adjusted mean difference: 11.2, 95% CI: 2.2–20.2). Seven percent of enrolled patients presented with high acuity (ICU‐level care in the first 72 h), and 16% had high toxicity (any ICU‐level care); there were no identifiable differences by income, refuting mediating roles in the association between income and HRQOL. Enrolled patients were less likely to be Black/African American (9.9% vs. 22.2%), more likely to be privately insured (50.4% vs. 40.7%), and more likely to have been treated on a clinical trial (26.7% vs. 18.5%) compared to eligible unenrolled patients not enrolled. Evaluations of potential selection bias on the association between income and HRQOL suggested differences in HRQOL may be smaller than observed or even in the opposing direction. Conclusions: While primary analyses suggested lower household income was associated with superior HRQOL, differential participation may have biased these results. Future studies should partner with patients/families to identify strategies for equitable participation in clinical research. [ABSTRACT FROM AUTHOR]

Background: Pediatric acute myeloid leukemia (AML) chemotherapy increases the risk of life‐threatening complications, including septic shock (SS). An area‐based measure of social determinants of health, the social disorganization index (SDI), was hypothesized to be associated with SS and SS‐associated death (SS‐death). Methods: Children treated for de novo AML on two Children's Oncology Group trials at institutions contributing to the Pediatric Health Information System (PHIS) database were included. The SDI was calculated via residential zip code data from the US Census Bureau. SS was identified via PHIS resource utilization codes. SS‐death was defined as death within 2 weeks of an antecedent SS event. Patients were followed from 7 days after the start of chemotherapy until the first of end of front‐line therapy, death, relapse, or removal from study. Multivariable‐adjusted Cox regressions estimated hazard ratios (HRs) comparing time to first SS by SDI group. Results: The assembled cohort included 700 patients, with 207 (29.6%) sustaining at least one SS event. There were 233 (33%) in the SDI‐5 group (highest disorganization). Adjusted time to incident SS did not statistically significantly differ by SDI (reference, SDI‐1; SDI‐2: HR, 0.84 [95% confidence interval (CI), 0.51–1.41]; SDI‐3: HR, 0.70 [95% CI, 0.42–1.16]; SDI‐4: HR, 0.97 [95% CI, 0.61–1.53]; SDI‐5: HR, 0.72 [95% CI, 0.45–1.14]). Nine patients (4.4%) with SS experienced SS‐death; seven of these patients (78%) were in SDI‐4 or SDI‐5. Conclusions: In a large, nationally representative cohort of trial‐enrolled pediatric patients with AML, there was no significant association between the SDI and time to SS. Time to first septic shock event was not associated with the social disorganization index (SDI), an area‐based measure of social determination of health, in children with acute myeloid leukemia treated on two Children's Oncology Group trials. Septic shock–associated mortality is rare in children with acute myeloid leukemia, and differences by SDI were not able to be detected. [ABSTRACT FROM AUTHOR]

Background: Despite the widespread implementation of telemedicine, there are limited data regarding its impact on key components of care for patients with incurable or high‐risk cancer. For these patients, high‐quality care requires detailed conversations regarding treatment priorities (advance care planning) and clinical care to minimize unnecessary acute care (unplanned hospitalizations). Whether telemedicine affects these outcomes relative to in‐person clinic visits was examined among patients with cancer at high risk for 6‐month mortality. Methods: This retrospective cohort study included adult patients with cancer with any tumor type treated at the University of Pennsylvania who were newly identified between April 1 and December 31, 2020, to be at high risk for 6‐month mortality via a validated machine learning algorithm. Separate modified Poisson regressions were used to assess the occurrence of advance care planning and unplanned hospitalizations for telemedicine as compared to in‐person visits. Additional analyses were done comparing telemedicine type (video or phone) as compared to in‐person clinic visits. Results: The occurrence of advance care planning was similar between telemedicine and in‐person visits (6.8% vs. 6.0%; adjusted risk ratio [aRR], 1.25; 95% CI, 0.92–1.69). In regard to telemedicine subtype, patients exposed to video encounters were modestly more likely to have documented advance care planning in comparison to those seen in person (7.5% vs. 6.0%; aRR, 1.48; 95% CI, 1.03–2.11). The 3‐month risk for unplanned hospitalization was comparable for telemedicine compared to in‐person clinic encounters (21% vs. 18%; aRR, 1.06; 95% CI, 0.81–1.38). Conclusions: In this study, care delivered by telemedicine, compared to in‐person clinic visits, produced comparable rates of advance care planning conversations without increasing hospitalizations, which suggests that vulnerable patients can be managed safely by telemedicine. In this study, care delivered by telemedicine, compared to in‐person clinic visits, produced comparable rates of advance care planning conversations without increasing hospitalizations, which suggests that vulnerable patients can be managed safely by telemedicine. [ABSTRACT FROM AUTHOR]

A multi‐arm trial allows simultaneous comparison of multiple experimental treatments with a common control and provides a substantial efficiency advantage compared to the traditional randomized controlled trial. Many novel multi‐arm multi‐stage (MAMS) clinical trial designs have been proposed. However, a major hurdle to adopting the group sequential MAMS routinely is the computational effort of obtaining total sample size and sequential stopping boundaries. In this paper, we develop a group sequential MAMS trial design based on the sequential conditional probability ratio test. The proposed method provides analytical solutions for futility and efficacy boundaries to an arbitrary number of stages and arms. Thus, it avoids complicated computational effort for the methods proposed by Magirr et al. Simulation results showed that the proposed method has several advantages compared to the methods implemented in R package MAMS by Magirr et al. [ABSTRACT FROM AUTHOR]

The employment of ultra‐thin lithium metal anode with high loading cathode is the key to realizing high‐energy‐density rechargeable lithium batteries. Ultra‐thin lithium foils are routinely loaded on a copper substrate in batteries, however, the close contact of these two metals causes galvanic corrosion in the presence of electrolyte, which results in irreversible consumption of lithium and decomposition of electrolyte. Herein, a lightweight and highly conductive flexible graphite paper (GP) is applied to replace Cu foil as the current collector for lithium metal anode. It is demonstrated that the application of GP prevents galvanic corrosion and maintains intimate and steady contact between Li foil and GP current collector during cycling, thereby improving the electrochemical performance of the battery. A 1.08 Ah pouch cell assembled with Li@GP anode and LiNi0.8Co0.1Mn0.1O2 cathode exhibits a long lifetime of 240 cycles with a capacity retention of 91.6% under limited Li, high cathode loading and lean electrolyte conditions. [ABSTRACT FROM AUTHOR]

Background: Timely targeted treatment initiation can be challenging because additional biomarker testing is needed for eligibility. The authors hypothesized that timely targeted treatment improves survival relative to nontimely initiation in metastatic HER2+ gastroesophageal adenocarcinoma (GEA). Methods: The authors performed a retrospective cohort study of metastatic HER2+ GEA treated with first‐line (1L) systemic therapy from January 2011 to December 2017 using a nationwide electronic health record–derived deidentified database. Timely targeted treatment—trastuzumab initiation within 14 days after starting 1L chemotherapy—was assessed as a time‐varying exposure. Nontimely targeted treatment included patients who initiated trastuzumab after 14 days or who lacked documentation of receiving trastuzumab. Extended Cox regressions compared overall survival (OS) and progression‐free survival (PFS) between timely and nontimely groups. Results: A total of 320 patients were included; 59.1% received timely trastuzumab. Relative to nontimely initiation, timely trastuzumab was associated with significantly higher OS (2‐year OS, 32.1% vs 15.3%; adjusted hazard ratio [HR], 0.67; 95% CI, 0.51‐0.88) and PFS (2‐year PFS, 9.2% vs 3.7%; adjusted HR, 0.71; 95% CI, 0.55‐0.93). Results remained similar in sensitivity analyses 1) using alternative "timeliness" definitions up to 70 days after starting 1L chemotherapy, 2) comparing any trastuzumab, regardless of timing of initiation, to no trastuzumab, and 3) excluding patients lacking documentation of receiving trastuzumab. Conclusions: Improved survival was observed among metastatic HER2+ GEA patients treated with trastuzumab versus those who were not, regardless of timing of initiation. Although these results reassure clinicians that modest targeted treatment delays may not be detrimental to outcomes, efforts should still ensure that all metastatic HER2+ GEA patients receive trastuzumab. Time‐to‐treatment initiation is an important quality metric in oncology, but there is a paucity of data on the impact of timely targeted treatment for which additional biomarker testing is needed to identify eligible patients. In this study of patients with metastatic HER2‐overexpressing gastroesophageal adenocarcinoma, overall and progression‐free survival rates were higher for patients treated with trastuzumab compared to those who were not, regardless of the timing of initiation. [ABSTRACT FROM AUTHOR]

This paper discusses the design of clinical trials where the primary endpoint is a recurrent event with the focus on the sample size calculation. For the problem, a few methods have been proposed but most of them assume a multiplicative treatment effect on the rate or mean number of recurrent events. In practice, sometimes the additive treatment effect may be preferred or more appealing because of its intuitive clinical meaning and straightforward interpretation compared to a multiplicative relationship. In this paper, new methods are presented and investigated for the sample size calculation based on the additive rates model for superiority, non‐inferiority, and equivalence trials. They allow for flexible baseline rate function, staggered entry, random dropout, and overdispersion in event numbers, and simulation studies show that the proposed methods perform well in a variety of settings. We also illustrate how to use the proposed methods to design a clinical trial based on real data. [ABSTRACT FROM AUTHOR]

BACKGROUND: Anti human epidermal growth factor receptor 2 (anti‐HER2) therapy with trastuzumab improves overall survival in patients with advanced, HER2‐positive gastroesophageal adenocarcinoma (GEA) and is now incorporated into national guidelines. However, little is known about adherence to and determinants of timely HER2 testing and trastuzumab initiation in routine practice. METHODS: The authors performed a cross‐sectional study of patients who had advanced GEA diagnosed between January 2011 and June 2019 in a nationwide electronic health record‐derived database. The annual prevalences of both timely HER2 testing (defined within 21 days after advanced diagnosis) and timely trastuzumab initiation (defined within 14 days after a positive HER2 result) were calculated. Log‐binomial regressions estimated adjusted prevalence ratios comparing timely HER2 testing and trastuzumab initiation by patient and tumor characteristics. RESULTS: In total, the cohort included 6032 patients with advanced GEA of whom 1007 were HER2‐positive. Between 2011 and 2019, timely HER2 testing increased from 22.4% to 44.5%, whereas timely trastuzumab initiation remained stable at 16.3%. No appreciable differences in timely testing or trastuzumab initiation were noted by age, sex, race, or insurance status. Compared with patients who had metastatic disease at diagnosis, patients who had early stage GEA who did not undergo surgery were less likely to receive timely HER2 testing and trastuzumab initiation (testing prevalence ratio, 0.69; 95% CI, 0.64‐0.75; treatment prevalence ratio, 0.32; 95% CI, 0.18‐0.56), as were patients with early stage disease who subsequently developed a distant recurrence (testing prevalence ratio, 0.56; 95% CI, 0.47‐0.65; treatment prevalence ratio, 0.61; 95% CI, 0.24‐1.55). CONCLUSIONS: In patients with advanced GEA, guideline‐recommended HER2 testing and anti‐HER2 therapy remain underused. Uptake may improve with universal HER2 testing regardless of stage. Timely HER2 biomarker testing and targeted therapy administration remain in use for patients with advanced gastroesophageal adenocarcinoma. Compared with patients initially diagnosed with de novo metastatic disease, those diagnosed with early stage disease who develop a recurrence or who do not undergo curative surgery are less likely to receive timely precision oncology care. [ABSTRACT FROM AUTHOR]

Despite the importance of adverse event (AE) reporting, AEs are under-reported on clinical trials. We hypothesized that electronic medical record (EMR) data can ascertain laboratory-based AEs more accurately than those ascertained manually. EMR data on 12 AEs for patients enrolled on two Children's Oncology Group (COG) trials at one institution were extracted, processed and graded. When compared to gold standard chart data, COG AE report sensitivity and positive predictive values (PPV) were 0-21·1% and 20-100%, respectively. EMR sensitivity and PPV were >98·2% for all AEs. These results demonstrate that EMR-based AE ascertainment and grading substantially improves laboratory AE reporting accuracy. [ABSTRACT FROM AUTHOR]

Background: Adolescents with cancer engage in sexual behaviors and are exposed to teratogenic chemotherapy. There are no data regarding pregnancy screening patterns for adolescents before chemotherapy exposure.Methods: A cross-sectional study of leukemia and emergency room (ER) admissions in the Pediatric Health Information System from 1999 to 2011 was conducted. Females who were 10 to 18 years old and 1) had newly diagnosed acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) or 2) had ER visits with computed tomography (CT) of the abdomen/pelvis were included. The exposure was a hospital visit with either chemotherapy or an abdominal/pelvic CT scan. The main outcome was a pregnancy test billed on the same day or before the teratogenic exposure within the same index admission. Log-binomial regressions were used to compute prevalence ratios and 95% confidence intervals comparing pregnancy screening in the leukemia and ER cohorts.Results: A total of 35,650 admissions were identified. The proportion of visits with an appropriately timed pregnancy test was 35%, 64%, and 58% in the ALL (n = 889), AML (n = 127), and ER cohorts (n = 34,634), respectively. Patients with ALL were significantly less likely to have a pregnancy test than the ER cohort (adjusted prevalence ratio, 0.71; 95% confidence interval, 0.65-0.78), but there was no significant difference between the AML and ER cohorts (adjusted prevalence ratio, 1.12; 95% confidence interval, 0.99-1.27). There was substantial hospital-level variation in pregnancy screening patterns.Conclusions: Adolescents with acute leukemia and ER visits have low rates of pregnancy screening before teratogenic exposures. Standardized practice guidelines for pregnancy screening among adolescents may improve screening rates. Cancer 2016;122:3394-3400. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Although inferior outcomes of children with Down syndrome ( DS) and acute lymphoid leukaemia ( ALL) are established, national supportive care patterns for these patients are unknown. A validated retrospective cohort of paediatric patients diagnosed with ALL from 1999 to 2011 was assembled from the US Pediatric Health Information System ( PHIS) database to examine organ toxicity, sepsis, and resource utilization in children with and without DS. Among 10699 ALL patients, 298 had DS- ALL (2·8%). In a multivariate model, DS was associated with increased risk of cardiovascular (odds ratio [ OR] 2·0, 95% confidence interval [ CI] 1·6-2·7), respiratory ( OR 2·1, 95% CI: 1·6-2·9), neurologic ( OR 3·4, 95% CI 1·9-6·2), and hepatic ( OR 1·4, 95% CI 1·0-1·9) dysfunction and sepsis ( OR 1·8, 95% CI: 1·4-2·4). Children with DS- ALL used significantly more respiratory support, insulin, and anti-infectives, including broad-spectrum Gram-positive agents, quinolones, and azoles. They used significantly fewer analgesics and antiemetics compared to non- DS- ALL children. Ultimately, this study confirms the increased risk of infectious and end-organ toxicity in children with DS- ALL and quantifies important differences in resource utilization between children with DS and non- DS ALL. These findings highlight the importance of investigating the impact of these care variations and developing specific supportive care guidelines for this population. [ABSTRACT FROM AUTHOR]

In oncology clinical trials, overall survival, time to progression, and progression-free survival are three commonly used endpoints. Empirical correlations among them have been published for different cancers, but statistical models describing the dependence structures are limited. Recently, Fleischer et al. proposed a statistical model that is mathematically tractable and shows some flexibility to describe the dependencies in a realistic way, based on the assumption of exponential distributions. This paper aims to extend their model to the more flexible Weibull distribution. We derived theoretical correlations among different survival outcomes, as well as the distribution of overall survival induced by the model. Model parameters were estimated by the maximum likelihood method and the goodness of fit was assessed by plotting estimated versus observed survival curves for overall survival. We applied the method to three cancer clinical trials. In the non-small-cell lung cancer trial, both the exponential and the Weibull models provided an adequate fit to the data, and the estimated correlations were very similar under both models. In the prostate cancer trial and the laryngeal cancer trial, the Weibull model exhibited advantages over the exponential model and yielded larger estimated correlations. Simulations suggested that the proposed Weibull model is robust for data generated from a range of distributions. [ABSTRACT FROM AUTHOR]

Objective: Our aim was to expand research on predictors of health-related quality of life (HRQOL) for adolescent and young adult survivors of childhood brain tumors who are not living independently by evaluating the mediating role of family functioning in the association of disease severity/treatment late effects with survivor self-report and caregiver-proxy report of physical and emotional HRQOL. Methods: Mothers (N= 186) and their survivors living at home (N= 126) completed self-report and caregiver-proxy report of physical and emotional HRQOL. Mothers completed family functioning measures of general family functioning, caregiving demands, and caregiver distress. Medical file review and caregiver report were used to evaluate disease severity/treatment late effects. Results: Using structural equation models, family functioning was adjusted for sociodemographic factors. Disease severity/treatment late effects had significant direct effects on self-report and caregiver-proxy report of physical and emotional HRQOL. Family functioning had a significant direct effect on caregiver-proxy report of physical and emotional HRQOL, but these findings were not confirmed for self-report HRQOL. Model-fit indices suggested good fit of the models, but the mediation effect of family functioning was not supported. Conclusions: Disease severity/treatment late effects explained self-report and caregiver-proxy report of physical and emotional HRQOL for these adolescent and young adult survivors of childhood brain tumors. Family functioning was implicated as an important factor for caregiver-proxy report only. To enhance physical and emotional HRQOL, findings underscore the importance of coordinated, multidisciplinary follow-up care for the survivors who are not living independently and their families to address treatment late effects and support family management. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims Smoking cessation trials generally record information on daily smoking behavior, but base analyses on measures of smoking status at the end of treatment (EOT). We present an alternative approach that analyzes the entire sequence of daily smoking status observations. Methods We analyzed daily abstinence data from a smoking cessation trial, using two longitudinal logistic regression methods: a mixed-effects (ME) model and a generalized estimating equations (GEE) model. We compared results to a standard analysis that takes abstinence status at EOT as outcome. We evaluated time-varying covariates (smoking history and time-varying drug effect) in the longitudinal analysis and compared ME and GEE approaches. Results We observed some differences in the estimated treatment effect odds ratios across models, with narrower confidence intervals under the longitudinal models. GEE yields similar results to ME when only baseline factors appear in the model, but gives biased results when one includes time-varying covariates. The longitudinal models indicate that the quit probability declines and the drug effect varies over time. Both the previous day's smoking status and recent smoking history predict quit probability, independently of the drug effect. Conclusion When analysing outcomes of studies from smoking cessation interventions, longitudinal models with multiple outcome data points, rather than just end of treatment, can makes efficient use of the data and incorporate time-varying covariates. The generalized estimating equations approach should be avoided when using time-varying predictors. [ABSTRACT FROM AUTHOR]

We propose a flexible parametric model to describe alternating states recurrent-event data where there is a possibility of cure with each type of event. We begin by introducing a novel cure model in which a common frailty influences both the cure probability and the hazard function given not cured. We then extend our model to data with recurring events of two alternating types. We assume that each type of event has a gamma frailty, and we link the frailties by a Clayton copula. We illustrate the model with an analysis of data from two smoking cessation trials comparing bupropion and placebo, in which each subject potentially experienced a series of lapse and recovery events. Our analysis suggests that bupropion increases the probability of permanent cure and decreases the hazard of lapse, but does not affect the distribution of time to recovery during a lapse. The data suggest a positive but non-significant association between the lapse and recovery frailties. A simulation study suggests that the estimates have little bias and that their 95 per cent confidence intervals have nearly nominal coverage in samples of practical size. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Using patient‐reported outcomes for symptom monitoring in oncology has resulted in significant benefits for adult patients with cancer. The feasibility of this approach has not been established in the routine care of children with cancer. Methods: The Pediatric Patient‐Reported Outcomes version of the Common Terminology Criteria for Adverse Events (Ped‐PRO‐CTCAE) is an item library that enables children and caregivers to self‐report symptoms. Ten symptom items from the Ped‐PRO‐CTCAE were uploaded to an online platform. Patients at least 7 years old and their caregivers were prompted by text/email message to electronically self‐report daily during a planned hospitalization for chemotherapy administration. Symptom reports were emailed to the clinical team caring for the patient, but no instructions were given regarding the use of this information. Rates of patient participation and clinician responses to reports were systematically tracked. Results: The median age of the participating patients (n = 52) was 11 years (range, 7‐18 years). All patients and caregivers completed an initial login, with 92% of dyads completing at least 1 additional symptom assessment during hospitalization (median, 3 assessments; range, 0‐40). Eighty‐one percent of participating dyads submitted symptom reports on at least half of hospital days, and 54% submitted reports on all hospital days. Clinical actions were taken in response to symptom reports 21% of the time. Most patients felt that the system was easy (73%) and important (79%). Most clinicians found symptom reports easy to understand and useful (97%). Conclusions: Symptom monitoring using patient‐reported outcome measures for hospitalized pediatric oncology patients is feasible and generates data valued by clinicians and patients. Patient‐ and caregiver‐reported symptom monitoring is feasible for children hospitalized for chemotherapy, and clinicians are willing to use patient‐reported symptom data to make clinical decisions. [ABSTRACT FROM AUTHOR]

The article offers information on a study related to the epidemiology of Recombinant urate oxidase (rasburicase) use in paediatric patients with acute lymphoblastic leukaemia and non-Hodgkin lymphoma. It notes the use of Pediatric Health Information System database (PHIS) for the study which include demographics, diagnosis codes and daily resource utilization data.

Abstract: Data routinely collected through United Network for Organ Sharing (UNOS) lack the detailed information on medical resource utilization and treatment costs required to accomplish for center‐level comparisons of quality of care and cost for pediatric heart transplantation. We aimed to overcome this limitation by merging UNOS with the Pediatric Health Information System (PHIS) database, an administrative database containing inpatient, emergency department, ambulatory surgery, and observation unit information from over 40 not‐for‐profit, tertiary care pediatric hospitals. Utilizing a probabilistic match based on center, date of birth, recipient gender, and transplant date within ±2 days, more than 90% of eligible UNOS patients (N = 2264) were successfully merged to their corresponding PHIS records. Thirty‐day and 1‐year mortality rates observed for the merged cohort (3.2% and 9.0%, respectively) were compared with those previously reported for pediatric heart transplants, as were the significant predictors of increased mortality. These results demonstrate that the established UNOS‐PHIS cohort will provide a valid platform for subsequent research aimed at identifying center‐level differences that could be exploited to optimize quality of care while minimizing cost across institutions. [ABSTRACT FROM AUTHOR]

Summary: Low light intensities affect the outbreak of plant diseases. However, the underlying molecular mechanisms remain poorly understood.High‐performance liquid chromatography analysis of tomato (Solanum lycopersicum) revealed that apoplastic glucose (Glc) levels decreased in response to low light. Conversely, low‐light‐induced susceptibility to Pseudomonas syringae pv tomato (Pst) DC3000 was significantly alleviated by exogenous Glc treatment. Using cell‐based biolayer interferometry assays, we found that Glc specifically binds to the tomato regulator of G protein signaling 1 (RGS1). Laser scanning confocal microscopy imaging revealed that Glc triggers RGS1 endocytosis, which influences the uncoupling of the RGS1‐Gα (GPA1) and GPA1‐Gβ (SlGB1) proteins, in a dose‑ and duration‐dependent manner.Analysis of G protein single and double mutants revealed that RGS1 negatively regulates disease resistance under low light and is required for Glc‐enhanced defense. Downstream of RGS1‐Glc binding, GPA1 negatively mediates the light‐intensity‐regulated defense, whereas SlGB1 positively regulates this process.These results reveal a novel light‐intensity‐responsive defense system that is mediated by a Glc–RGS1–G protein signaling pathway. This information will be critical for future investigations of how plant cells sense extracellular sugars and adjust defense under different environments, as well as for genetic engineering approaches to improve stress resilience. [ABSTRACT FROM AUTHOR]

In addition to dichotomous measures of abstinence, smoking studies may use daily cigarette consumption as an outcome variable. These counts hold the promise of more efficient and detailed analyses than dichotomous measures, but present serious quality issues - measurement error and heaping - if obtained by retrospective recall. A doubly-coded dataset with a retrospective recall measurement (timeline followback, TLFB) and a more precise instantaneous measurement (ecological momentary assessment, EMA) serves as a calibration dataset, allowing us to predict EMA given TLFB and baseline factors. We apply this model to multiply impute precise cigarette counts for a randomized, placebo-controlled trial of bupropion with only TLFB measurements available. To account for repeated measurements on a subject, we induce correlation in the imputed counts. Finally, we analyze the imputed data in a longitudinal model that accommodates random subject effects and zero inflation. Both raw and imputed data show a significant drug effect for reducing the odds of non-abstinence and the number of cigarettes smoked among non-abstainers, but the imputed data provide efficiency gains. This method permits the analysis of daily cigarette consumption data previously deemed suspect due to reporting error and is applicable to other self-reported count data sets for which calibration samples are available. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Most cancer deaths result from progression of therapy resistant disease, yet our understanding of this phenotype is limited. Cancer therapies generate stress signals that act upon mitochondria to initiate apoptosis. Mitochondria isolated from neuroblastoma cells were exposed to tBid or Bim, death effectors activated by therapeutic stress. Multidrug‐resistant tumor cells obtained from children at relapse had markedly attenuated Bak and Bax oligomerization and cytochrome c release (surrogates for apoptotic commitment) in comparison with patient‐matched tumor cells obtained at diagnosis. Electron microscopy identified reduced ER–mitochondria‐associated membranes (MAMs; ER–mitochondria contacts, ERMCs) in therapy‐resistant cells, and genetically or biochemically reducing MAMs in therapy‐sensitive tumors phenocopied resistance. MAMs serve as platforms to transfer Ca2+ and bioactive lipids to mitochondria. Reduced Ca2+ transfer was found in some but not all resistant cells, and inhibiting transfer did not attenuate apoptotic signaling. In contrast, reduced ceramide synthesis and transfer was common to resistant cells and its inhibition induced stress resistance. We identify ER–mitochondria‐associated membranes as physiologic regulators of apoptosis via ceramide transfer and uncover a previously unrecognized mechanism for cancer multidrug resistance. Synopsis: Longitudinal analysis of patient‐derived tumor cell lines identifies reduced levels of ER–mitochondria‐associated membranes (MAMs; ER–mitochondria contacts, ERMCs) as a novel contributor to multidrug resistance in childhood neuroblastoma. Mitochondria from drug‐resistant neuroblastoma cells exhibit attenuated apoptotic signal transduction, cytochrome c release, and MAMs.Transfer of Ca2+ from MAMs to mitochondria is not required for reduced apoptosis in therapy‐resistant cells.Disruption of ceramide biosynthesis at MAMs and of lipid transfer to the outer mitochondrial membrane decreases apoptotic signaling and enhances multidrug resistance in relapsed cells. [ABSTRACT FROM AUTHOR]

Purpose: To generate synthetic relative proton stopping power (sRPSP) images from magnetic resonance imaging (MRI) sequence(s) and develop an online quality assurance (QA) tool for sRPSP to facilitate safe integration of magnetic resonance (MR)‐only proton planning into clinical practice. Materials and methods: Planning computed tomography (CT) and MR images of 195 pediatric brain tumor patients were utilized (training: 150, testing: 45). Seventeen consistent‐cycle generative adversarial network (ccGAN) models were trained separately using paired CT‐converted RPSP and MRI datasets to transform a subject's MRI into sRPSP. T1‐weighted (T1W), T2‐weighted (T2W), and FLAIR MRI were permutated to form 17 combinations, with or without preprocessing, for determining the optimal training sequence(s). For evaluation, sRPSP images were converted to synthetic CT (sCT) and compared to the real CT in terms of mean absolute error (MAE) in Hounsfield units (HU). For QA, sCT was deformed and compared to a reference template built from training dataset to produce a flag map, highlighting pixels that deviate by >100 HU and fall outside the mean ± standard deviation reference intensity. The gamma intensity analysis (10%/3 mm) of the deformed sCT against the QA template on the intensity difference was investigated as a surrogate of sCT accuracy. Results: The sRPSP images generated from a single T1W or T2W sequence outperformed that generated from multi‐MRI sequences in terms of MAE (all p < 0.05). Preprocessing with N4 bias and histogram matching reduced MAE of T2W MRI‐based sCT (54 ± 21 HU vs. 42 ± 13 HU, p = 0.002). The gamma intensity analysis of sCT against the QA template was highly correlated with the MAE of sCT against the real CT in the testing cohort (r = ‐0.89 for T1W sCT; r = ‐0.93 for T2W sCT). Conclusion: Accurate sRPSP images can be generated from T1W/T2W MRI for proton planning. A QA tool highlights regions of inaccuracy, flagging problematic cases unsuitable for clinical use. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the feasibility and accuracy of magnetic resonance imaging (MRI)-based treatment planning using pseudo CTs generated through atlas registration. Methods: A pseudo CT, providing electron density information for dose calculation, was generated by deforming atlas CT images previously acquired on other patients. The authors tested 4 schemes of synthesizing a pseudo CT from single or multiple deformed atlas images: use of a single arbitrarily selected atlas, arithmetic mean process using 6 atlases, and pattern recognition with Gaussian process (PRGP) using 6 or 12 atlases. The required deformation for atlas CT images was derived from a nonlinear registration of conjugated atlas MR images to that of the patient of interest. The contrasts of atlas MR images were adjusted by histogram matching to reduce the effect of different sets of acquisition parameters. For comparison, the authors also tested a simple scheme assigning the Hounsfield unit of water to the entire patient volume. All pseudo CT generating schemes were applied to 14 patients with common pediatric brain tumors. The image similarity of real patient-specific CT and pseudo CTs constructed by different schemes was compared. Differences in computation times were also calculated. The real CT in the treatment planning system was replaced with the pseudo CT, and the dose distribution was recalculated to determine the difference. Results: The atlas approach generally performed better than assigning a bulk CT number to the entire patient volume. Comparing atlas-based schemes, those using multiple atlases outperformed the single atlas scheme. For multiple atlas schemes, the pseudo CTs were similar to the real CTs (correlation coefficient, 0.787-0.819). The calculated dose distribution was in close agreement with the original dose. Nearly the entire patient volume (98.3%-98.7%) satisfied the criteria of chi-evaluation (<2% maximum dose and 2 mm range). The dose to 95% of the volume and the percentage of volume receiving at least 95% of the prescription dose in the planning target volume differed from the original values by less than 2% of the prescription dose (root-mean-square, RMS < 1%). The PRGP scheme did not perform better than the arithmetic mean process with the same number of atlases. Increasing the number of atlases from 6 to 12 often resulted in improvements, but statistical significance was not always found. Conclusions: MRI-based treatment planning with pseudo CTs generated through atlas registration is feasible for pediatric brain tumor patients. The doses calculated from pseudo CTs agreed well with those from real CTs, showing dosimetric accuracy within 2% for the PTV when multiple atlases were used. The arithmetic mean process may be a reasonable choice over PRGP for the synthesis scheme considering performance and computational costs. [ABSTRACT FROM AUTHOR]

BACKGROUND: Clinical trials in pediatric acute myeloid leukemia (AML) determine induction regimen standards. However, these studies lack the data necessary to evaluate mortality trends over time and differences in resource utilization between induction regimens. Moreover, these trials likely underreport the clinical toxicities experienced by patients. METHODS: The Pediatric Health Information System database was used to identify children treated for presumed de novo AML between 1999 and 2010. Induction mortality, risk factors for induction mortality, and resource utilization by induction regimen were estimated using standard frequentist statistics, logistic regression, and Poisson regression, respectively. RESULTS: A total of 1686 patients were identified with an overall induction case fatality rate of 5.4% that decreased from 9.8% in 2003 to 2.1% in 2009 ( P = .0023). The case fatality rate was 9.0% in the intensively timed DCTER (dexamethasone, cytarabine, thioguanine, etoposide, and rubidomycin [daunomycin]/idarubicin) induction and 3.8% for ADE (cytarabine, daunomycin, and etoposide) induction (adjusted odds ratio = 2.2, 95% confidence interval = 1.1-4.5). Patients treated with intensively timed DCTER regimens had significantly greater antibiotic, red cell/platelet transfusion, analgesic, vasopressor, renal replacement therapy, and radiographic resource utilization than patients treated with ADE regimens. Resource utilization was substantially higher than reported in published pediatric AML clinical trials. CONCLUSIONS: Induction mortality for children with AML decreased significantly as ADE use increased. In addition to higher associated mortality, intensively timed DCTER regimens had a correspondingly higher use of health care resources. Using resource utilization data as a proxy for adverse events, adverse event rates reported on clinical trials substantially underestimated the clinical toxicities of all pediatric AML induction regimens. Cancer 2013. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

We consider longitudinal discrete data that may be unequally spaced in time and may exhibit overdispersion, so that the variance of the outcome variable is inflated relative to its assumed distribution. We implement an approach that extends generalized linear models for analysis of longitudinal data and is likelihood based, in contrast to generalized estimating equations (GEE) that are semiparametric. The method assumes independence between subjects; first‐order antedependence within subjects; exponential family distributions for the first outcome on each subject and for the subsequent conditional distributions; and linearity of the expectations of the conditional distributions. We demonstrate application of the method in an analysis of seizure counts and in a study to evaluate the performance of transplant centers. Simulations for both studies demonstrate the benefits of the proposed likelihood based approach; however, they also demonstrate better than anticipated performance for GEE. [ABSTRACT FROM AUTHOR]

Purpose: Despite cure, adolescents and young adults (AYA) who complete cancer treatment remain at risk for numerous physical and psychological late effects. However, engagement in recommended follow-up care, knowledge of cancer treatment history and risks, and adoption of health promoting behaviors are often suboptimal. The pilot randomized controlled trial assessed the feasibility and acceptability of a text messaging intervention (THRIVE; Texting Health Resources to Inform, motiVate, and Engage) designed to promote well-being, and health knowledge and behaviors.Methods: Sixty-one AYA who recently completed cancer therapy enrolled and were randomized to receive THRIVE (n = 31) or an AYA survivor handbook (n = 30). Participants from both groups completed baseline measures and follow-up surveys 16 weeks later. AYA randomized to THRIVE received one to two health-related text messages per day over 16 weeks.Results: THRIVE demonstrated a high level of acceptability and feasibility. Exploratory analyses highlighted promising improvements in knowledge, fruit/vegetable intake, and perceptions of health vulnerability.Conclusions: Text messaging is an acceptable and feasible intervention approach for improving well-being and health of AYA survivors. Future research is needed to test the impact of text messaging in a larger trial, including whether or not such an intervention can improve clinical outcomes, such as survivors' engagement in follow-up care. [ABSTRACT FROM AUTHOR]

Previous data suggest that patients enrolled on clinical trials for treatment of cancer have better overall survival than patients who do not enroll; however, short-term outcomes relative to trial enrollment and corresponding mediators have not been assessed. A cohort of pediatric patients with newly-diagnosed acute myeloid leukemia was assembled from the Pediatric Health Information System. We evaluated whether patients not enrolled onto Children's Oncology Group trial AAML0531 had greater intensive care unit ( ICU)-level requirements than enrolled patients and whether early discharge after chemotherapy administration mediated this association. Patients not enrolled on AAML0531 were more likely to be discharged early ( aOR = 1.40, 95% confidence interval [ CI]: 1.02, 1.90) and to require ICU-level care ( aOR = 2.00, 95% CI: 1.06, 3.78) than enrolled patients, but early discharge explained only a small proportion (12.3%) of the absolute difference in ICU-level care risk. The direct effect of nonenrollment on the need for ICU-level care was significant ( aOR = 1.89, 95% CI: 1.00, 3.94), whereas the indirect effect mediated through early discharge was not ( aOR = 1.07, 95% CI: 0.95, 1.19). Factors other than postchemotherapy discharge strategy drive the difference in ICU utilization by trial enrollment status. [ABSTRACT FROM AUTHOR]

The article offers information on a study on the treatment of primary adrenal insufficiency with basal steroid replacement and supplemental glucocorticoids during periods of medical stress. Topics discussed include the difference between primary and central adrenal insufficiency, the need for supplemental glucocorticoids for pediatric patients with adrenal insufficiency, hypothalamic/pituitary injury from tumor growth, surgical resection, and/or radiation therapy, and logit link method.

Comparisons of early discharge and outpatient postchemotherapy supportive care in pediatric acute myeloid leukemia ( AML) patients are limited. We used data from the Pediatric Health Information System on a cohort of children treated for newly diagnosed AML to compare course-specific mortality and resource utilization in patients who were discharged after chemotherapy to outpatient management during neutropenia relative to patients who remained hospitalized. Patients were categorized at each course as early or standard discharge. Discharges within 3 days after chemotherapy completion were considered 'early'. Resource utilization was determined based on daily billing data and reported as days of use per 1000 hospital days. Inpatient mortality, occurrence of intensive care unit ( ICU)-level care, and duration of hospitalization were compared using logistic, log-binomial and linear regression methods, respectively. Poisson regression with inpatient days as offset was used to compare resource use by discharge status. The study population included 996 patients contributing 2358 treatment courses. Fewer patients were discharged early following Induction I (7%) than subsequent courses (22-24%). Across courses, patients discharged early experienced high readmission rates (69-84%), yet 9-12 fewer inpatient days (all P < 0.001). Inpatient mortality was low across courses and did not differ significantly by discharge status. The overall risk for ICU-level care was 116% higher for early compared to standard discharge patients (adjusted risk ratio: 2.16, 95% confidence interval: 1.50, 3.11). Rates of antibiotic, vasopressor, and supplemental oxygen use were consistently elevated for early discharge patients. Despite similar inpatient mortality to standard discharge patients, early discharge patients may be at greater risk for life-threatening chemotherapy-related complications, including infections. [ABSTRACT FROM AUTHOR]

An efficient method for synthesis of useful biaryl building blocks containing thienyl or pyridyl moieties is provided through cross-coupling reactions of freshly prepared heteroaryl aluminum reagents with aryl bromides or benzyl halides. [ABSTRACT FROM AUTHOR]

Establishing the normative range of age-dependent fluorodeoxyglucose (FDG) uptake in the developing brain is necessary for understanding regional quantitative analysis of positron emission tomography (PET) brain images in children and also to provide functional information on brain development. We analyzed head sections of FDG PET/computed tomography (CT) images for 115 patients (5 months to 23 years) without central nervous system disease before treatment, as PET studies are not performed on healthy children owing to ethical considerations and the risk of radiation exposure. We investigated the changes in FDG uptake and established age-associated normative ranges of cerebral FDG. Head sections of FDG PET/CT images were registered to a population-based probabilistic atlas of human cortical structures. Gray matter of 56 brain structures was defined on normalized PET images according to the atlas. To avoid individual and experimental confounding factors, the relative standardized uptake value (SUV) over the cerebellum of each structure was calculated. Relative SUVs were analyzed by ANOVA and modeled using generalized estimating equalization analysis with false discovery rate control. Age and structure were significant factors affecting SUVs. Anatomic proximity had little effect on FDG uptake. Linear and quadratic developmental trajectories were observed on absolute and relative SUVs, respectively. An increase from posterior-to-anterior and superior-to-inferior pattern was observed in both absolute SUV increase rate and relative SUV peak age. The SUV of each structure was modeled with respect to age, and these models can serve as baselines for the quantitative analysis of cerebral FDG-PET images of children. Hum Brain Mapp 35:2297-2309, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The bone marrow failure syndromes ( BMFS) are a heterogeneous group of rare blood disorders characterized by inadequate haematopoiesis, clonal evolution, and increased risk of leukaemia. Single nucleotide polymorphism arrays ( SNP-A) have been proposed as a tool for surveillance of clonal evolution in BMFS. To better understand the natural history of BMFS and to assess the clinical utility of SNP-A in these disorders, we analysed 124 SNP-A from a comprehensively characterized cohort of 91 patients at our BMFS centre. SNP-A were correlated with medical histories, haematopathology, cytogenetic and molecular data. To assess clonal evolution, longitudinal analysis of SNP-A was performed in 25 patients. We found that acquired copy number-neutral loss of heterozygosity ( CN- LOH) was significantly more frequent in acquired aplastic anaemia ( aAA) than in other BMFS (odds ratio 12·2, P < 0·01). Homozygosity by descent was most common in congenital BMFS, frequently unmasking autosomal recessive mutations. Copy number variants ( CNVs) were frequently polymorphic, and we identified CNVs enriched in neutropenia and aAA. Our results suggest that acquired CN- LOH is a general phenomenon in aAA that is probably mechanistically and prognostically distinct from typical CN- LOH of myeloid malignancies. Our analysis of clinical utility of SNP-A shows the highest yield of detecting new clonal haematopoiesis at diagnosis and at relapse. [ABSTRACT FROM AUTHOR]

A series of optically active pyridyl methanols is available with the title reaction. [ABSTRACT FROM AUTHOR]

An abstract of the article "Copper-Catalyzed Electrophilic Amination of Organoaluminum Nucleophiles with O-Benzoyl Hydroxylamines" by Shuangliu Zhou and colleagues is presented.