The Children's Oncology Group study AREN0534 aimed to improve event-free survival (EFS) and overall survival (OS) while preserving renal tissue by intensifying preoperative chemotherapy, completing ...definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histologic response.
No prospective therapeutic clinic trials in children with bilateral Wilms tumors (BWT) exist. Historical outcomes for this group were poor and often involved prolonged chemotherapy; on NWTS-5, 4-year EFS for all children with BWT was 56%.
Patients were enrolled and imaging studies were centrally reviewed to assess for bilateral renal lesions. They were treated with 3-drug induction chemotherapy (vincristine, dactinomycin, and doxorubicin) for 6 or 12 weeks based on radiographic response followed by surgery and further chemotherapy determined by histology. Radiation therapy was provided for postchemotherapy stage III and IV disease.
One hundred eighty-nine of 208 patients were evaluable. Four-year EFS and OS were 82.1% (95% CI: 73.5%-90.8%) and 94.9% (95% CI: 90.1%-99.7%. Twenty-three patients relapsed and 7 had disease progression. After induction chemotherapy 163 of 189 (84.0%) underwent definitive surgical treatment in at least 1 kidney by 12 weeks and 39% retained parts of both kidneys. Surgical approaches included: unilateral total nephrectomy with contralateral partial nephrectomy (48%), bilateral partial nephrectomy (35%), unilateral total nephrectomy (10.5%), unilateral partial nephrectomy (4%), and bilateral total nephrectomies (2.5%).
This treatment approach including standardized 3-drug preoperative chemotherapy, surgical resection within 12 weeks of diagnosis and response and histology-based postoperative therapy improved EFS and OS and preservation of renal parenchyma compared with historical outcomes for children with BWT.
As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. ...Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15-informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants’ effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues atwhich variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for NUDT15 variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.
Genetic testing for neurodegenerative diseases (NDs) is highly challenging because of genetic heterogeneity and overlapping manifestations. Targeted-gene panels (TGPs), coupled with next-generation ...sequencing (NGS), can facilitate the profiling of a large repertoire of ND-related genes. Due to the technical limitations inherent in NGS and TGPs, short tandem repeat (STR) variations are often ignored. However, STR expansions are known to cause such NDs as Huntington's disease and spinocerebellar ataxias type 3 (SCA3). Here, we studied the clinical utility of a custom-made TGP that targets 199 NDs and 311 ND-associated genes on 118 undiagnosed patients. At least one known or likely pathogenic variation was found in 54 patients; 27 patients demonstrated clinical profiles that matched the variants; and 16 patients whose original diagnosis were refined. A high concordance of variant calling were observed when comparing the results from TGP and whole-exome sequencing of four patients. Our in-house STR detection algorithm has reached a specificity of 0.88 and a sensitivity of 0.82 in our SCA3 cohort. This study also uncovered a trove of novel and recurrent variants that may enrich the repertoire of ND-related genetic markers. We propose that a combined comprehensive TGPs-bioinformatics pipeline can improve the clinical diagnosis of NDs.
A scarlet fever outbreak occurred in Hong Kong in 2011. The majority of cases resulted in the isolation of Streptococcus pyogenes emm12 with multiple antibiotic resistances. Phylogenetic analysis of ...22 emm12 scarlet fever outbreak isolates, 7 temporally and geographically matched emm12 non-scarlet fever isolates, and 18 emm12 strains isolated during 2005-2010 indicated the outbreak was multiclonal. Genome sequencing of 2 nonclonal scarlet fever isolates (HKU16 and HKU30), coupled with diagnostic polymerase chain reaction assays, identified 2 mobile genetic elements distributed across the major lineages: a 64.9-kb integrative and conjugative element encoding tetracycline and macrolide resistance and a 46.4-kb prophage encoding superantigens SSA and SpeC and the DNase Spd1. Phenotypic comparison of HKU16 and HKU30 with the S. pyogenes M1T1 strain 5448 revealed that HKU16 displays increased adherence to HEp-2 human epithelial cells, whereas HKU16, HKU30, and 5448 exhibit equivalent resistance to neutrophils and virulence in a humanized plasminogen murine model. However, in contrast to M1T1, the virulence of HKU16 and HKU30 was not associated with covRS mutation. The multiclonal nature of the emm12 scarlet fever isolates suggests that factors such as mobile genetic elements, environmental factors, and host immune status may have contributed to the 2011 scarlet fever outbreak.
High dynamic range (HDR) video compression technology, which is capable of delivering a wider range of luminance and a larger colour gamut than standard dynamic range (SDR) technology, has been ...widely used in recent years in many fields, including industrial image processing, digital entertainment, and machine vision. Rate control (RC) is of paramount importance to HDR compression and transmission; accordingly, an RC scheme for HDR in High Efficiency Video Coding (HEVC) is proposed in this paper. First, considering the HDR characteristics, we propose an HDR-Visual Difference Predictor (VDP)-2-based rate-distortion (R-D) model to improve the coding performance. Second, we directly utilize <inline-formula> <tex-math notation="LaTeX">\lambda </tex-math></inline-formula> rather than the bit rate in the optimization process to obtain the optimal solution. Finally, we propose a new model parameter estimation method to further reduce the RC errors. According to our experimental results, significant bit rate reductions in terms of HDR-VDP-2, the Video Quality Metric (VQM) and the mean peak-signal-to-noise ratio (mPSNR) can be achieved on average compared with the state-of-the-art algorithm used in HM16.19.
Background: To evaluate the use of high-density silicone oil (HDSO) as a tamponade agent for retinal detachment secondary to myopic macular hole. Methods: 12 eyes of 12 patients with macular hole ...retinal detachment underwent pars plana vitrectomy, internal limiting membrane peeling and HDSO tamponade. No posturing was required postoperatively and HDSO was removed 3–4 months later. Outcome measures included macular hole closure and retinal attachment rates, best-corrected visual acuity (BCVA), and intraoperative and postoperative complications. Results: The mean age of the patients was 67.8 years and the mean spherical equivalent refractive error was −13.4 diopters. After the removal of HDSO, 10 (83%) eyes had macular hole closure with retinal reattachment without any tamponade. One eye had retinal reattachment after re-operation and the other refused further surgery. At the last follow-up, the median BCVA improved from 20/800 to 20/600 (p = 0.046). A transient increase in intraocular pressure was observed in 5 (42%) eyes and one eye each developed mild oil emulsification and transient peripheral choroidal detachment. None of the eyes was found to have severe intraocular inflammation postoperatively. Conclusions: HDSO seemed to be an effective tamponade agent for myopic macular hole retinal detachment. Further prospective controlled studies seem warranted.
Different from the conventional calculative methods, a learning-based initial quantization parameter (LIQP) method is proposed in this paper to improve rate control of high efficiency video coding ...(H.265). First, the framework for initial quantization parameter (QP) learning is proposed, where a novel equivalent approach to build the benchmark labels is proposed using the single rate-distortion (R-D) pair in each initial QP testing. With the criterion of maximizing the prediction accuracy of initial QPs, features and parameters of the learning model are refined. Instead of the traditionally used target bits per pixel (bpp) for intraframe, the target bpp for all remaining frames is proposed to avoid the empirical setting on intracoding bits, and thus the related inaccuracy can be prevented. We clearly present the motivations of the proposed LIQP method, as well as the reasons for the extracted features and model parameters. The proposed LIQP method outperforms the latest HM-16.14 by achieving significant gains on R-D performance (−15.48% BD-BR and 0.782 dB BD-PSNR gains), quality smoothness (1.581 dB versus 2.598 dB), and more stable buffer occupancy control, with similar high bit rate accuracy (99.84% versus 99.87%), and can also work well for scene change cases.
Inter-individual variance in 6-mercaptopurine (6-MP) dose intensity is common in patients with acute lymphoblastic leukemia (ALL). We aimed to evaluate the association of common variants of ABCC4, ...ITPA, NUDT15, and TPMT with 6-MP dose intensity and toxicity in pediatric ALL patients. In this cohort, 13.8% of patients were intolerant to 6-MP with actual dosage less than 50% of scheduled dose. Twenty percent of patients were found to be heterozygous or homozygous mutated with NUDT15. NUDT15 c.415C > T and the genotype-predicted NUDT15 activity were significantly associated with 6-MP intolerance. TPMT*3C variants were not common in this cohort (2.8%). NUDT15 polymorphisms and genotype predicted NUDT15 activity were significantly associated with 6-MP dose intensity and leukopenia episodes. Combination of ABCC4 and ITPA variants (ABCC4 c.912G > T and ITPA c.94C > A) also showed significant positive association with 6-MP intolerance in Chinese children with ALL. Further study on pharmacogenetic screening for ALL patients to avoid 6-MP induced toxicity is recommended.
Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2021.1973628
In order to improve the flame retardant of polylactide (PLA), the synergistic effect of graphitic carbon nitride (g‐C3N4) with commercial‐available flame retardants melamine pyrophosphate (MPP) and ...9,10‐dihydro‐9‐oxa‐10‐phosphaphenanthrene‐10‐oxide (DOPO) was investigated. The PLA composites containing 5 wt% g‐C3N4 and 10 wt% DOPO had a highest limited oxygen index (LOI) value of 29.5% and reached the V‐0 rating of UL‐94 test. The cone calorimeter tests exhibited that DOPO had a better synergistic effect with g‐C3N4 than MPP to improve flame retardancy of PLA. The peak heat release rate (pHRR) and total heat release (THR) of PLA composites containing 10 wt% DOPO could be reduced by 25.2% and 23.6%, respectively, as compared with those of pure PLA. The presence of rich phosphorus element and aromatic groups in DOPO contributed to obtain continuous compact char layer and increase the graphitization level of char residues, thereby, resulting in improving the flame retardancy of PLA together with g‐C3N4. In addition, the incorporation of DOPO can serve as a plasticizer to reduce the complex viscosity, improving the processability of PLA composites.
In a survey of elderly Chinese aged 70 years and over living in Hong Kong selected by stratified random sampling, the prevalence of depression was determined using the 15-item Geriatric Depression ...Scale using a cut-off point of 8 (sensitivity 96.3% and specificity 87.5% for this population). Subjects with moderate to severe cognitive impairment (CAPE I/O score < or = 7) were excluded. There were 877 men and 734 women. The adjusted overall prevalence for this population was 29.2% for men and 41.1% for women. The prevalence increased with age in men and was higher in women than in men. Univariate analysis identified many factors in the following areas that were associated with depression: socioeconomic characteristics, functional ability, physical health and social support. Stepwise logistic regression identified 16 factors predictive of depression: socioeconomic characteristics, such as borderline living expenses and dissatisfaction with living arrangement; poor social support, such as absence of an informal carer when ill, few relatives to turn to, and infrequent contact with neighbours and friends; functional disability, as indicated by a Barthel Index < 15, urinary incontinence and inability to do housework; and poor physical health--poor self perceived health, poor vision, difficulty with chewing, history of mental illness, frequent hospital admissions and increased level of symptoms such as poor memory, constipation and dizziness. Some of these factors may be amenable to intervention, and such measures may be important in reducing the high prevalence of depression in elderly people.
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