Publications

BACKGROUND

Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking.

METHODS

In a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial.

RESULTS

Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events.

CONCLUSIONS

Among young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen. (Funded by the National Institutes of Health; AVICA ClinicalTrials.gov number, NCT01606319.).

Distressing symptoms are associated with poor function, acute care use, and mortality in older adults. The number of older jail inmates is increasing rapidly, prompting calls to develop systems of care to meet their healthcare needs, yet little is known about multidimensional symptom burden in this population. This cross-sectional study describes the prevalence and factors associated with distressing symptoms and the overlap between different forms of symptom distress in 125 older jail inmates in an urban county jail. Physical distress was assessed using the Memorial Symptom Assessment Scale. Several other forms of symptom distress were also examined, including psychological (Generalized Anxiety Disorder Scale, Patient Health Questionnaire), existential (Patient Dignity Inventory), and social (Three Item Loneliness Scale). Information was collected on participant sociodemographic characteristics, multimorbidity, serious mental illness (SMI), functional impairment, and behavioral health risk factors through self-report and chart review. Chi-square tests were used to identify factors associated with physical distress. Overlap between forms of distress was evaluated using set theory analysis. Overall, many participants (74%) reported distressing symptoms, including having one or more physical (44%), psychological (37%), existential (54%), or social (45%) symptoms. Physical distress was associated with poor health (multimorbidity, functional impairment, SMI) and low income. Of the 93 participants with any symptom, 49% reported three or more forms of distress. These findings suggest that an optimal model of care for this population would include a geriatrics-palliative care approach that integrates the management of all forms of symptom distress into a comprehensive treatment paradigm stretching from jail to the community.

BACKGROUND

Many widely used myocardial T1 mapping sequences use breath-hold acquisitions that limit the precision of calculated T1 maps. The SAturation-recovery single-SHot Acquisition (SASHA) sequence has high accuracy with robustness against systematic confounders, but has poorer precision compared to the commonly used MOdified Look-Locker Inversion recovery (MOLLI) sequence. We propose a novel method for generating high-contrast SASHA images to enable a robust image registration approach to free-breathing T1 mapping with high accuracy and precision.

METHODS

High-contrast (HC) images were acquired in addition to primary variable flip angle (VFA) SASHA images by collecting an additional 15 k-space lines and sharing k-space data with the primary image. The number of free-breathing images and their saturation recovery times were optimized through numerical simulations. Accuracy and precision of T1 maps using the proposed SASHA-HC sequence was compared in 10 volunteers at 1.5 T to MOLLI, a breath-hold SASHA-VFA sequence, and free-breathing SASHA-VFA data processed using conventional navigator gating and standard image registration. Free-breathing T1 maps from 15 patients and 10 volunteers were graded by blinded observers for sharpness and artifacts.

RESULTS

Difference images calculated by subtracting HC and primary SASHA images had greater tissue-blood contrast than the primary images alone, with a 3× improvement for 700 ms TS saturation recovery images and a 6× increase in tissue-blood contrast for non-saturated images. Myocardial T1s calculated in volunteers with free-breathing SASHA-HC were similar to standard breath-hold SASHA-VFA (1156.1 ± 28.1 ms vs 1149.4 ± 26.5 ms, p >0.05). The standard deviation of myocardial T1 values using a 108 s free-breathing SASHA-HC (36.2 ± 3.1 ms) was 50 % lower (p <0.01) than breath-hold SASHA-VFA (72.7 ± 8.0 ms) and 34 % lower (p <0.01) than breath-hold MOLLI (54.7 ± 5.9 ms). T1 map quality scores in volunteers were higher with SASHA-HC (4.7 ± 0.3 out of 5) than navigator gating (3.6 ± 0.4, p <0.01) or normal registration (3.7 ± 0.4, p <0.01). SASHA-HC T1 maps had comparable precision to breath-hold MOLLI using a retrospectively down-sampled 30 s free-breathing acquisition and 30 % higher precision with a 60 s acquisition.

CONCLUSIONS

High-contrast SASHA images enable a robust image registration approach to free-breathing T1 mapping. Free-breathing SASHA-HC provides accurate T1 maps with higher precision than MOLLI in acquisitions longer than 30 s.

Homeobox (HOX) proteins and the receptor tyrosine kinase FLT3 are frequently highly expressed and mutated in acute myeloid leukemia (AML). Aberrant HOX expression is found in nearly all AMLs that harbor a mutation in the Nucleophosmin (NPM1) gene, and FLT3 is concomitantly mutated in approximately 60% of these cases. Little is known about how mutant NPM1 (NPM1) cells maintain aberrant gene expression. Here, we demonstrate that the histone modifiers MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1 AML. Using a CRISPR/Cas9 genome editing domain screen, we show NPM1 AML to be exceptionally dependent on the menin binding site in MLL1. Pharmacologic small-molecule inhibition of the menin-MLL1 protein interaction had profound antileukemic activity in human and murine models of NPM1 AML. Combined pharmacologic inhibition of menin-MLL1 and DOT1L resulted in dramatic suppression of HOX and FLT3 expression, induction of differentiation, and superior activity against NPM1 leukemia.

SIGNIFICANCE

MLL1 and DOT1L are chromatin regulators that control HOX, MEIS1, and FLT3 expression and are therapeutic targets in NPM1 AML. Combinatorial small-molecule inhibition has synergistic on-target activity and constitutes a novel therapeutic concept for this common AML subtype. Cancer Discov; 6(10); 1166-81. ©2016 AACR.See related commentary by Hourigan and Aplan, p. 1087This article is highlighted in the In This Issue feature, p. 1069.