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Sickle cell disease (SCD) decreases the oxygen-carrying capacity of red blood cells. Children with SCD have reduced/restricted cerebral blood flow, resulting in neurocognitive deficits. Hydroxyurea is the standard treatment for SCD; however, whether hydroxyurea influences such effects is unclear. A key area of SCD-associated neurocognitive impairment is working memory, which is implicated in other cognitive and academic skills. The neural correlates of working memory can be tested using n-back tasks. We analyzed functional magnetic resonance imaging (fMRI) data of patients with SCD (20 hydroxyurea-treated patients and 11 controls, aged 7–18 years) while they performed n-back tasks. Blood-oxygenation level–dependent (BOLD) signals were assessed during working memory processing at 2 time points: before hydroxyurea treatment and ~1 year after treatment was initiated. Neurocognitive measures were also assessed at both time points. Our results suggested that working memory was stable in the treated group. We observed a treatment-by-time interaction in the right cuneus and angular gyrus for the 2- >0-back contrast. Searchlight-pattern classification of the 2 time points of the 2-back tasks identified greater changes in the pattern and magnitude of BOLD signals, especially in the posterior regions of the brain, in the control group than in the treated group. In the control group at 1-year follow-up, 2-back BOLD signals increased across time points in several clusters (e.g., right inferior temporal lobe, right angular gyrus). We hypothesize that these changes resulted from increased cognitive effort during working memory processing in the absence of hydroxyurea. In the treated group, 0- to 2-back BOLD signals in the right angular gyrus and left cuneus increased continuously with increasing working memory load, potentially related to a broader dynamic range in response to task difficulty and cognitive effort. These findings suggest that hydroxyurea treatment helps maintain working memory function in SCD. [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]

Traditional two-arm randomized trial designs have played a pivotal role in establishing the efficacy of medical interventions. However, their efficiency is often compromised when confronted with multiple experimental treatments or limited resources. In response to these challenges, the multi-arm multi-stage designs have emerged, enabling the simultaneous evaluation of multiple treatments within a single trial. In such an approach, if an arm meets efficacy success criteria at an interim stage, the whole trial stops and the arm is selected for further study. However when multiple treatment arms are active, stopping the trial at the moment one arm achieves success diminishes the probability of selecting the best arm. To address this issue, we have developed a group sequential multi-arm multi-stage survival trial design with an arm-specific stopping rule. The proposed method controls the familywise type I error in a strong sense and selects the best promising treatment arm with a high probability. [ABSTRACT FROM AUTHOR]

A PENTEC (Pediatric Normal Tissue Effects in the Clinic) review was performed to estimate the dose-volume effects of radiation therapy on spine deformities and growth impairment for patients who underwent radiation therapy as children. A systematic literature search was performed to identify published data for spine deformities and growth stunting. Data were extracted from 12 reports of children irradiated to the spine (N = 603 patients). The extracted data were analyzed to find associations between complication risks and the radiation dose (conventional fractionation throughout) as impacted by exposed volumes and age using the mixed-effects logistic regression model. When appropriate, corrections were made for radiation modality, namely orthovoltage beams. In the regression analysis, the association between vertebral dose and scoliosis rate was highly significant (P <.001). Additionally, young age at time of radiation was highly predictive of adverse outcomes. Clinically significant scoliosis can occur with doses ≥15 Gy to vertebrae during infancy (<2 years of age). For children irradiated at 2 to 6 years of age, overall scoliosis rates of any grade were >30% with doses >20 Gy; grade 2 or higher scoliosis was correlated with doses ≥30 Gy. Children >6 years of age remain at risk for scoliosis with doses >30 Gy; however, most cases will be mild. There are limited data regarding the effect of dose gradients across the spine on degree of scoliosis. The risk of clinically meaningful height loss was minimal when irradiating small volumes of the spine up to 20 Gy (eg, flank irradiation), except in infants who are more vulnerable to lower doses. Growth stunting was more frequent when larger segments of the spine (eg, the entire spine or craniospinal irradiation) were irradiated before puberty to doses >20 Gy. The effect was modest when patients were irradiated after puberty to doses >20 Gy. To reduce the risk of kyphoscoliosis and growth impairment, the dose to the spine should be kept to <20 Gy for children <6 years of age and to <10 to 15 Gy in infants. The number of vertebral bodies irradiated and dose gradients across the spine should also be limited when possible. [ABSTRACT FROM AUTHOR]

Mutations in HNRNPH2 cause an X-linked neurodevelopmental disorder with features that include developmental delay, motor function deficits, and seizures. More than 90% of patients with hnRNPH2 have a missense mutation within or adjacent to the nuclear localization signal (NLS) of hnRNPH2. Here, we report that hnRNPH2 NLS mutations caused reduced interaction with the nuclear transport receptor Kapβ2 and resulted in modest cytoplasmic accumulation of hnRNPH2. We generated 2 knockin mouse models with human-equivalent mutations in Hnrnph2 as well as Hnrnph2-KO mice. Knockin mice recapitulated clinical features of the human disorder, including reduced survival in male mice, impaired motor and cognitive functions, and increased susceptibility to audiogenic seizures. In contrast, 2 independent lines of Hnrnph2-KO mice showed no detectable phenotypes. Notably, KO mice had upregulated expression of Hnrnph1, a paralog of Hnrnph2, whereas knockin mice failed to upregulate Hnrnph1. Thus, genetic compensation by Hnrnph1 may counteract the loss of hnRNPH2. These findings suggest that HNRNPH2-related disorder may be driven by a toxic gain of function or a complex loss of HNRNPH2 function with impaired compensation by HNRNPH1. The knockin mice described here are an important resource for preclinical studies to assess the therapeutic benefit of gene replacement or knockdown of mutant hnRNPH2. [ABSTRACT FROM AUTHOR]