Recommendations for assessing cognitive risks in young children treated for ependymoma for clinical and research protocols: evidence from a systematic literature review

Background: Current treatment approaches for pediatric ependymoma differ between North American and European studies. Post-surgical adjuvant irradiation is used in children aged <36 months in North America, whilst European approaches use chemotherapy to avoid or defer radiotherapy until three years of age, in order to avoid late neurocognitive toxicity. To establish evidence for the effects of cranial radiotherapy in children aged <36 months with ependymoma on neurocognitive outcomes, we conducted a systematic literature review assessing methodological approaches for measuring neurocognitive outcome. Methods: Eight databases were selected to perform an advanced search, retrieval and systematic review of papers describing neurocognitive outcome in children diagnosed with ependymoma who received cranial radiotherapy at <36 months. Results: Limitations of published data permitted descriptive analysis only. Considerable variation in reporting survival rates, techniques and timing of psychometric testing and the results of neurocognitive outcomes was identified. Conclusions: The review identified significant inconsistencies of neurocognitive testing, particularly literacy skills, developmental time points for testing and methods of data reporting. The role of the cerebellum for cognitive development, especially reading, has been inadequately evaluated in published studies. Recommendations are made to improve assessment methods, and time points for testing, so that reports do not fail to identify children who acquire deficits as they mature through childhood and adolescence. We conclude that claims that radiation treatment for ependymoma administered aged <36 months is associated with limited neurocognitive consequences, are not supported by the literature

A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children's Cancer Study Group Investigation

A phase I study of nolatrexed, administered as a continuous 5 day intravenous infusion every 28 days, has been undertaken for children with advanced malignancy. 16 patients were treated at 3 dose levels; 420, 640 and 768 mg/m2 24 h−1. 8 patients were evaluable for toxicity. In the 6 patients treated at 768 mg/m2 24 h−1, dose-limiting oral mucositis and myelosuppression were observed. Plasma nolatrexed concentrations and systemic exposure, measured in 14 patients, were dose related, with mean AUC values of 36 mg−1 ml−1 min−1, 50 mg ml−1 min−1 and 80 mg ml−1 min−1at the 3 dose levels studied. Whereas no toxicity was encountered if the nolatrexed AUC was <45 mg ml−1 min−1, Grade 3 or 4 toxicity was observed with AUC values of >60 mg ml−1 min−1. Elevated plasma deoxyuridine levels, measured as a surrogate marker of thymidylate synthase inhibition, were seen at all of the dose levels studied. One patient with a spinal primitive neuroectodermal tumour had stable disease for 11 cycles of therapy, and in two patients with acute lymphoblastic leukaemia a short-lived 50% reduction in peripheral lymphoblast counts was observed. Nolatrexed can be safely administered to children with cancer, and there is evidence of therapeutic activity as well as antiproliferative toxicity. Phase II studies of nolatrexed in children at the maximum tolerated dose of 640 mg/m2 24 h−1are warranted. © 2001 Cancer Research Campaign http://www.bjcancer.co

The management of tetanus in adults in an intensive care unit in Southern Vietnam

Background: Tetanus remains common in many low- and middle-income countries (LMICs) yet the evidence base guiding management of this disease is extremely limited, particularly with respect to contemporary management options. Sharing knowledge about practice may facilitate improvement in outcomes elsewhere. Methods: We describe clinical interventions and outcomes of 180 adult patients ≥16 years-old with tetanus enrolled in prospective observational studies at a specialist infectious diseases hospital in Southern Vietnam. Patients were treated according to a holistic management protocol encompassing wound-care, antitoxin, antibiotics, symptom control, airway management, nutrition and de-escalation criteria. Results: Mortality rate in our cohort was 2.8%, with 90 (50%) patients requiring mechanical ventilation for a median 16 [IQR 12-24] days. Median [IQR] duration of ICU stay was 15 [8-23] days. Autonomic nervous system dysfunction occurred in 45 (25%) patients. Hospital acquired infections occurred in 77 (43%) of patients. Conclusion: We report favourable outcomes for patients with tetanus in a single centre LMIC ICU, treated according to a holistic protocol. Nevertheless, many patients required prolonged intensive care support and hospital acquired infections were common

An Empirical Study of Bots in Software Development -- Characteristics and Challenges from a Practitioner's Perspective

Software engineering bots - automated tools that handle tedious tasks - are increasingly used by industrial and open source projects to improve developer productivity. Current research in this area is held back by a lack of consensus of what software engineering bots (DevBots) actually are, what characteristics distinguish them from other tools, and what benefits and challenges are associated with DevBot usage. In this paper we report on a mixed-method empirical study of DevBot usage in industrial practice. We report on findings from interviewing 21 and surveying a total of 111 developers. We identify three different personas among DevBot users (focusing on autonomy, chat interfaces, and "smartness"), each with different definitions of what a DevBot is, why developers use them, and what they struggle with. We conclude that future DevBot research should situate their work within our framework, to clearly identify what type of bot the work targets, and what advantages practitioners can expect. Further, we find that there currently is a lack of general purpose "smart" bots that go beyond simple automation tools or chat interfaces. This is problematic, as we have seen that such bots, if available, can have a transformative effect on the projects that use them.Comment: To be published at the ACM Joint European Software Engineering Conference and Symposium on the Foundations of Software Engineering (ESEC/FSE

A pipeline for high throughput detection and mapping of SNPs from EST databases

Single nucleotide polymorphisms (SNPs) represent the most abundant type of genetic variation that can be used as molecular markers. The SNPs that are hidden in sequence databases can be unlocked using bioinformatic tools. For efficient application of these SNPs, the sequence set should be error-free as much as possible, targeting single loci and suitable for the SNP scoring platform of choice. We have developed a pipeline to effectively mine SNPs from public EST databases with or without quality information using QualitySNP software, select reliable SNP and prepare the loci for analysis on the Illumina GoldenGate genotyping platform. The applicability of the pipeline was demonstrated using publicly available potato EST data, genotyping individuals from two diploid mapping populations and subsequently mapping the SNP markers (putative genes) in both populations. Over 7000 reliable SNPs were identified that met the criteria for genotyping on the GoldenGate platform. Of the 384 SNPs on the SNP array approximately 12% dropped out. For the two potato mapping populations 165 and 185 SNPs segregating SNP loci could be mapped on the respective genetic maps, illustrating the effectiveness of our pipeline for SNP selection and validation

Reduced renal length and volume 20 years after very preterm birth

Intrauterine growth retardation is presumed to be associated with decreased renal size and impaired renal function as a result of stunted kidney development and nephron deficit. To study whether very preterm birth also affects renal size at young adulthood, we sonographically measured bipolar kidney length and volume in 51 very premature individuals (<32 weeks of gestation), either small (SGA) or appropriate (AGA) for gestational age (22 SGA and 29 AGA), and 30 full-term controls 20 years after birth. Relative kidney length and volume were calculated. Both absolute and relative left kidney length and volume were significantly lower in SGA and AGA individuals, notably in women. Renal size did not differ between SGA and AGA individuals. In 70% of controls, the left kidney was larger than the right one compared with 40.9% in SGA [relative risk (RR) 1.7; 95% confidence interval (CI) 1.0−3.0] and 48.3% in AGA (RR 1.5; 95% CI 0.9−2.3) individuals. Renal structural anomalies were present in eight prematurely born participants only. Our data suggest that kidney growth is stunted after preterm birth, especially on the left side, and in the female gender

A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours

Anthracyclines are widely used in paediatric oncology, but their use is limited by the risk of cumulative cardiac toxicity. Encapsulating anthracyclines in liposomes may reduce cardiac toxicity and possibly increase drug availability to tumours. A phase I study in paediatric patients was designed to establish the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) after a single course of liposomal daunorubicin, ‘DaunoXome', as a 1 h infusion on day 1 of a 21 day cycle. Patients were stratified into two groups according to prior treatment: Group A (conventional) and group B (heavily pretreated patients). Dose limiting toxicity was expected to be haematological, and a two-step escalation was planned, with and without G-CSF support. Pharmacokinetic studies were carried out in parallel. In all, 48 patients aged from 1 to 18 years were treated. Dose limiting toxicity was neutropenia for both groups. Maximum tolerated dose was defined as 155 mg m−2 for Group A and 100 mg m−2 for Group B. The second phase with G-CSF was interrupted because of evidence of cumulative cardiac toxicity. Cardiac toxicity was reported in a total of 15 patients in this study. DaunoXome shares the early cardiotoxicity of conventional anthracyclines in paediatric oncology. This study has successfully defined a haematological MTD for DaunoXome, but the significance of this is limited given the concerns of delayed cardiac toxicity. The importance of longer-term follow-up in patients enrolled into phase I studies has been underestimated previously, and may lead to an under-recognition of important adverse events