Universality of critical active site glutamate as an acid-base catalyst in serine hydroxymethyltransferase function.

Serine hydroxymethyltransferase (SHMT) is a key enzyme in the one-carbon metabolic pathway, utilizing the vitamin B6 derivative pyridoxal 5'-phosphate (PLP) and vitamin B9 derivative tetrahydrofolate (THF) coenzymes to produce essential biomolecules. Many types of cancer utilize SHMT in metabolic reprogramming, exposing the enzyme as a compelling target for antimetabolite chemotherapies. In pursuit of elucidating the catalytic mechanism of SHMT to aid in the design of SHMT-specific inhibitors, we have used room-temperature neutron crystallography to directly determine the protonation states in a model enzyme Thermus thermophilus SHMT (TthSHMT), which exhibits a conserved active site compared to human mitochondrial SHMT2 (hSHMT2). Here we report the analysis of TthSHMT, with PLP in the internal aldimine form and bound THF-analog, folinic acid (FA), by neutron crystallography to reveal H atom positions in the active site, including PLP and FA. We observed protonated catalytic Glu53 revealing its ability to change protonation state upon FA binding. Furthermore, we obtained X-ray structures of TthSHMT-Gly/FA, TthSHMT-l-Ser/FA, and hSHMT2-Gly/FA ternary complexes with the PLP-Gly or PLP-l-Ser external aldimines to analyze the active site configuration upon PLP reaction with an amino acid substrate and FA binding. Accurate mapping of the active site protonation states together with the structural information gained from the ternary complexes allow us to suggest an essential role of the gating loop conformational changes in the SHMT function and to propose Glu53 as the universal acid-base catalyst in both THF-independent and THF-dependent activities of SHMT.

Structural Snapshots of Proteus vulgaris Tryptophan Indole-Lyase Reveal Insights into the Catalytic Mechanism.

Tryptophan indole lyase (TIL; [E.C. 4.1.99.1]) is a bacterial pyridoxal-5'-phosphate (PLP)-dependent enzyme that catalyzes reversible ß-elimination of indole from L-tryptophan. The mechanism of elimination of indole from L-tryptophan starts with the formation of an external aldimine of the substrate and PLP, followed by deprotonation of the α-CH of the substrate, forming a resonance-stabilized quinonoid intermediate. Proton transfer to C3 of the indole ring and carbon-carbon bond cleavage of the quinonoid intermediate provide indole and aminoacrylate bound to PLP, which then releases indole, followed by iminopyruvate. We have now determined the X-ray crystal structures of TIL complexes with (3S)-dioxindolyl-l-alanine, an inhibitor, and with substrates L-tryptophan, 7-aza-L-tryptophan, and S-ethyl-l-cysteine (SEC) in the presence of benzimidazole (BZI), an isostere of the product indole. These structures show a mixture of gem-diamine, external aldimine, quinonoid, and aminoacrylate intermediates, in both open and closed active site conformations. In the closed conformations of L-tryptophan, (3S)-dioxindolyl-l-alanine, and 7-aza-L-tryptophan complexes, hydrogen bonds form between Asp-133 with N1 of the ligand heterocyclic ring and NE2 of His-458 in the small domain of TIL. This hydrogen bond also forms in the BZI complex with the aminoacrylate intermediates formed from both L-tryptophan and SEC. The closed quinonoid complex of 7-aza-L-tryptophan shows that the azaindole ring in the closed conformation is bent out of plane of the Cß-C3 bond by about 40°, putting it in a geometry that leads toward the transition-state geometry. Thus, both conformational dynamics and substrate activation play critical roles in the reaction mechanism of the TIL.

Mechanistic implications of the ternary complex structural models for the photoenzyme protochlorophyllide oxidoreductase.

The photoenzyme protochlorophyllide oxidoreductase (POR) is an important enzyme for understanding biological H-transfer mechanisms. It uses light to catalyse the reduction of protochlorophyllide to chlorophyllide, a key step in chlorophyll biosynthesis. Although a wealth of spectroscopic data have provided crucial mechanistic insight, a structural rationale for POR photocatalysis has proved challenging and remains hotly debated. Recent structural models of the ternary enzyme-substrate complex, derived from crystal and electron microscopy data, show differences in the orientation of the protochlorophyllide substrate and the architecture of the POR active site, with significant implications for the catalytic mechanism. Here, we use a combination of computational and experimental approaches to investigate the compatibility of each structural model with the hypothesised reaction mechanisms and propose an alternative structural model for the cyanobacterial POR ternary complex. We show that a strictly conserved tyrosine, previously proposed to act as the proton donor in POR photocatalysis, is unlikely to be involved in this step of the reaction but is crucial for Pchlide binding. Instead, an active site cysteine is important for both hydride and proton transfer reactions in POR and is proposed to act as the proton donor, either directly or through a water-mediated network. Moreover, a conserved glutamine is important for Pchlide binding and ensuring efficient photochemistry by tuning its electronic properties, likely by interacting with the central Mg atom of the substrate. This optimal 'binding pose' for the POR ternary enzyme-substrate complex illustrates how light energy can be harnessed to facilitate enzyme catalysis by this unique enzyme.

Revealing protonation states and tracking substrate in serine hydroxymethyltransferase with room-temperature X-ray and neutron crystallography.

Pyridoxal 5'-phosphate (PLP)-dependent enzymes utilize a vitamin B6-derived cofactor to perform a myriad of chemical transformations on amino acids and other small molecules. Some PLP-dependent enzymes, such as serine hydroxymethyltransferase (SHMT), are promising drug targets for the design of small-molecule antimicrobials and anticancer therapeutics, while others have been used to synthesize pharmaceutical building blocks. Understanding PLP-dependent catalysis and the reaction specificity is crucial to advance structure-assisted drug design and enzyme engineering. Here we report the direct determination of the protonation states in the active site of Thermus thermophilus SHMT (TthSHMT) in the internal aldimine state using room-temperature joint X-ray/neutron crystallography. Conserved active site architecture of the model enzyme TthSHMT and of human mitochondrial SHMT (hSHMT2) were compared by obtaining a room-temperature X-ray structure of hSHMT2, suggesting identical protonation states in the human enzyme. The amino acid substrate serine pathway through the TthSHMT active site cavity was tracked, revealing the peripheral and cationic binding sites that correspond to the pre-Michaelis and pseudo-Michaelis complexes, respectively. At the peripheral binding site, the substrate is bound in the zwitterionic form. By analyzing the observed protonation states, Glu53, but not His residues, is proposed as the general base catalyst, orchestrating the retro-aldol transformation of L-serine into glycine.

Using Evidence-Based Medicine to Support Clinical Decision-Making in RMS.

The foundations of evidence-based practice are the triad of patient values and preferences, healthcare professional experience, and best available evidence, used together to inform clinical decision-making. Within the field of rhabdomyosarcoma, collaborative groups such as the European Paediatric Soft Tissue Sarcoma Group (EpSSG) have worked to develop evidence to support this process. We have explored many of the key research developments within this review, including patient and public involvement, decision-making research, research into areas other than drug development, core outcome sets, reporting and dissemination of research, evidence synthesis, guideline development and clinical decision rules, research of research methodologies, and supporting research in RMS.

Severity of COVID-19 in children with cancer: Report from the United Kingdom Paediatric Coronavirus Cancer Monitoring Project.

BACKGROUND: Children with cancer are frequently immunocompromised. While children are generally thought to be at less risk of severe SARS-CoV-2 infection than adults, comprehensive population-based evidence for the risk in children with cancer is unavailable. We aimed to produce evidence of the incidence and outcomes from SARS-CoV-2 in children with cancer attending all hospitals treating this population across the UK. METHODS: Retrospective and prospective observational study of all children in the UK under 16 diagnosed with cancer through data collection from all hospitals providing cancer care to this population. Eligible patients tested positive for SARS-CoV-2 on reverse transcription polymerase chain reaction (RT-PCR). The primary end-point was death, discharge or end of active care for COVID-19 for those remaining in hospital. RESULTS: Between 12 March 2020 and 31 July 2020, 54 cases were identified: 15 (28%) were asymptomatic, 34 (63%) had mild infections and 5 (10%) moderate, severe or critical infections. No patients died and only three patients required intensive care support due to COVID-19. Estimated incidence of hospital identified SARS-CoV-2 infection in children with cancer under 16 was 3%. CONCLUSIONS: Children with cancer with SARS-CoV-2 infection do not appear at increased risk of severe infection compared to the general paediatric population. This is reassuring and supports the continued delivery of standard treatment.

A systematic review of evidence for and against routine surveillance imaging after completing treatment for childhood extracranial solid tumors.

BACKGROUND: Regular off-treatment imaging is often used to assess for recurrence of disease after childhood cancer treatment. It is unclear if this increases survival, or what burden surveillance places on patients, families, or health-care services. This systematic review examines the impact of routine surveillance imaging after treatment of pediatric extracranial solid tumors. METHODS: Collaborative patient and public involvement informed the design and interpretation of this work. Thirteen electronic databases, conference proceedings, and trial registries were searched alongside reference list checking and forward citation searching from 1990 onwards. Studies were screened and data were extracted by two researchers. Risk of bias was assessed using a modified ROBINS-I tool. Relevant outcomes were overall survival, psychological distress indicators, number of imaging tests, cost-effectiveness, and qualitative data regarding experiences of surveillance programs. PROSPERO (CRD42018103764). RESULTS: Of 17 727 records identified, 55 studies of 10 207 patients were included. All studies used observational methods. Risk of bias for all except one study was moderate, serious, or critical. Data were too few to conduct meta-analysis; however, narrative synthesis was performed. Surveillance strategies varied, and poorly reported, involving many scans and substantial radiation exposure (eg, neuroblastoma, median 133.5 mSv). For most diseases, surveillance imaging was not associated with increased overall survival, with the probable exception of Wilms tumor. No qualitative or psychological distress data were identified. CONCLUSIONS: At present, there is insufficient evidence to evaluate the effects of routine surveillance imaging on survival in most pediatric extracranial solid tumors. More high-quality data are required, preferably through randomized controlled trials with well-conducted qualitative elements.

Sharing Roles and Control in Pediatric Low Risk Febrile Neutropenia: A Multicenter Focus Group Discussion Study Involving Patients, Parents, and Health Care Professionals.

INTRODUCTION: Reducing treatment intensity for pediatric low risk febrile neutropenia may improve quality of life, and reduce hospital-acquired infections and costs. Key stakeholders' attitudes toward early discharge regimens are unknown. This study explored perceptions of reduced therapy regimens in the United Kingdom. MATERIALS AND METHODS: Three study sites were purposively selected for their approaches to risk stratification, treatment protocols, shared care networks, and geographical spread of patients. Patients aged 13 to 18 years, parents of children of all ages and health care professionals participated in focus group discussions. A constant comparison analysis was used. RESULTS: Thirty-two participants spoke of their different roles in managing febrile neutropenia and how these would change if reduced therapy regimens were implemented, how mutual trust would need to be strengthened and responsibility redistributed. Having identified a need for discretion and a desire for individualized care, negotiation within a spectrum of control allows achievement of the potential for realized discretion. Nonattendance exemplifies when control is different and families use their assessments of risk and sense of mutual trust, along with previous experiences, to make decisions. CONCLUSIONS: The significance of shared decision making in improving patient experience through sharing risks, developing mutual trust, and negotiating control to achieve individualized treatment cannot be underestimated.

Research priorities for young people with cancer: a UK priority setting partnership with the James Lind Alliance.

OBJECTIVES: To conduct a UK-wide survey of young people who have experienced cancer, carers and professionals, to identify and prioritise research questions to inform decisions of research funders and support the case for research with this unique cancer population. DESIGN: James Lind Alliance Priority Setting Partnership. SETTING: UK health service and community. METHODS: A steering group oversaw the initiative and partner organisations were recruited. Unanswered questions were collected in an online survey. Evidence searching verified uncertainties. An interim survey was used to rank questions prior to a final prioritisation workshop. PARTICIPANTS: Young people aged 13-24 years with a current or previous cancer diagnosis, their families, friends, partners and professionals who work with this population. RESULTS: Two hundred and ninety-two respondents submitted 855 potential questions. Following a refining process and removal of 'out of scope' questions, 208 unique questions remained. Systematic evidence checking identified seven answered questions and 16 were the subject of ongoing studies. The interim survey was completed by 174 participants. The top 30 questions were prioritised at a workshop attended by 25 young people, parents and multidisciplinary professionals. The top three priorities are: (1) What psychological support package improves psychological well-being, social functioning and mental health during and after treatment? (2) What interventions, including self-care, can reduce or reverse adverse short-term and long-term effects of cancer treatment? (3) What are the best strategies to improve access to clinical trials? The remaining questions reflect the complete cancer pathway: new therapies, life after cancer, support, education/employment, relapse and end-of-life care. CONCLUSIONS: We have identified shared research priorities for young people with cancer using a rigorous, person-centred approach involving stakeholders typically not involved in setting the research agenda. The breadth of priorities suggest future research should focus on holistic and psychosocial care delivery as well as traditional drug/biology research.

Does routine surveillance imaging after completing treatment for childhood solid tumours cause more harm than good? A systematic review and meta-analysis protocol.

BACKGROUND: This systemic review aims to synthesise the current literature surrounding off-therapy surveillance imaging in children and young people with extra-cranial solid tumours, with a view to establishing if routine imaging studies after treatment for childhood cancer increase overall survival, increase the psychological distress caused to patients and families, result in other harms to patients and are cost-effective strategies. Within this manuscript, we also describe how patient and public involvement has impacted upon the protocol. METHODS: The search will cover thirteen different databases, key conference proceedings and trial registers, as well as reference lists and forward citations of included papers. Prominent authors/clinicians in the field will be contacted. A full search strategy is provided. The study designs to be included in the review will be added in an iterative way (RCTs, quasi-randomised trials, prospective cohorts and retrospective cohorts). Qualitative studies will also be eligible for inclusion. We will include studies which examine a programme of surveillance imaging that aims to detect relapse in children or young people up to age 25 years who have completed treatment for a malignant extracranial solid tumour and have no evidence of active and ongoing disease at end of treatment. The primary outcome is overall survival, with secondary outcomes including psychological distress indicators, number of imaging tests performed, other harms of imaging and cost-effectiveness measures. Studies will be screened and data extracted by two researchers. Studies will be critically appraised using a stratified version of the ROBINS-I tool. Where appropriate, data will be synthesised using a random effects meta-analysis. A detailed analysis plan, including assessment of heterogeneity and publication bias, is provided. DISCUSSION: The aim of routine surveillance imaging is to detect recurrence of disease before clinical symptoms and signs develop. Some studies have suggested that most relapses of childhood cancer are detected due to clinical symptoms or signs, particularly in those with extra-cranial solid tumours, and when these relapses are detected by imaging, there is no increase in survival. This review aims to establish whether routine surveillance imaging is beneficial, as well as evaluating the potential negative impacts of surveillance programmes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018103764.

Updated systematic review and meta-analysis of the predictive value of serum biomarkers in the assessment and management of fever during neutropenia in children with cancer.

Routinely measurable biomarkers as predictors for adverse outcomes in febrile neutropenia could improve management through risk stratification. This systematic review assesses the predictive role of biomarkers in identifying events such as bacteraemia, clinically documented infections, microbiologically documented infection, severe sepsis requiring intensive care or high dependency care and death. This review collates 8319 episodes from 4843 patients. C-reactive protein (CRP), interleukin (IL)-6, IL-8 and procalcitonin (PCT) consistently predict bacteraemia and severe sepsis; other outcomes have highly heterogeneous results. Performance of the biomarkers at admission using different thresholds demonstrates that PCT > 0.5 ng/mL offers the best compromise between sensitivity and specificity: sensitivity 0.67 (confidence interval [CI] 0.53-0.79) specificity 0.73 (CI 0.66-0.77). Seventeen studies describe the use of serial biomarkers, with PCT having the greatest discriminatory role. Biomarkers, potentially with serial measurements, may predict adverse outcomes in paediatric febrile neutropenia and their role in risk stratification is promising.

Brincidofovir as a Salvage Therapy in Controlling Adenoviremia in Pediatric Recipients of Hematopoietic Stem Cell Transplant.

Adenovirus infection is a well-known complication in patients receiving hematopoietic stem cell transplantation (HSCT). Brincidofovir (BCV) is an orally bioavailable lipid conjugate of cidofovir, which has activity against adenoviruses. We present a review of adenovirus infections treated with BCV which were unresponsive to cidofovir initially in 4 patients and it was used upfront in one patient. Children with adenovirus infection following HSCT treated with BCV, between July 2014 and February 2018 were recognized. Five patients including 3 male and 2 female with a median age of 10 years (range, 2.2 to 10 y) were identified. The median days of adenoviremia detection was 18 days (range, 7 to 303 d) posttransplant. The median peak viral load by quantitative polymerase chain reaction was 21,38,000 copies/mL (range, 1,77,200 to 31,97,000 copies/mL). The median time from first detection of adenoviremia to become negative was 30 days (range, 15 to 113 d). The sites involved were gastrointestinal tract in all patients and 2 patients had additional respiratory tract involvement. Two patients survived and 3 patients died of sepsis. All patients responded well to BCV and no adverse effect was noticed. We saw the good safety profile and excellent antiadenoviral activity of BCV in pediatric patients receiving HSCT without the nephrotoxicity and it may have a role in preemptive therapy.

Nonneutropenic fever in children with cancer: A scoping review of management and outcome.

To date, very few studies have addressed nonneutropenic fever (NNF) in children with cancer, and there are no consensus guidelines. This scoping review aims to describe the rate of bacteremia, risk factors for infection and management, and outcomes of NNF in this population. Across 15 studies (n = 4106 episodes), the pooled-average bacteremia rate was 8.2%, and risk factors included tunneled external central venous catheter, clinical instability, and higher temperature. In two studies, antibiotics were successfully withheld in a subset of low-risk patients. Overall outcomes of NNF appear favorable; however, further research is required to determine its true clinical and economic impact.

The crystal structure of Proteus vulgaris tryptophan indole-lyase complexed with oxindolyl-L-alanine: implications for the reaction mechanism.

Tryptophan indole-lyase (TIL) is a bacterial enzyme which catalyzes the reversible formation of indole and ammonium pyruvate from L-tryptophan. Oxindolyl-L-alanine (OIA) is an inhibitor of TIL, with a Ki value of about 5 µM. The crystal structure of the complex of Proteus vulgaris TIL with OIA has now been determined at 2.1 Šresolution. The ligand forms a closed quinonoid complex with the pyridoxal 5'-phosphate (PLP) cofactor. The small domain rotates about 10° to close the active site, bringing His458 into position to donate a hydrogen bond to Asp133, which also accepts a hydrogen bond from the heterocyclic NH of the inhibitor. This brings Phe37 and Phe459 into van der Waals contact with the aromatic ring of OIA. Mutation of the homologous Phe464 in Escherichia coli TIL to Ala results in a 500-fold decrease in kcat/Km for L-tryptophan, with less effect on the reaction of other nonphysiological ß-elimination substrates. Stopped-flow kinetic experiments of F464A TIL show that the mutation has no effect on the formation of quinonoid intermediates. An aminoacrylate intermediate is observed in the reaction of F464A TIL with S-ethyl-L-cysteine and benzimidazole. A model of the L-tryptophan quinonoid complex with PLP in the active site of P. vulgaris TIL shows that there would be a severe clash of Phe459 (∼1.5 Šapart) and Phe37 (∼2 Šapart) with the benzene ring of the substrate. It is proposed that this creates distortion of the substrate aromatic ring out of plane and moves the substrate upwards on the reaction coordinate towards the transition state, thus reducing the activation energy and accelerating the enzymatic reaction.

Meta-ethnography of experiences of early discharge, with a focus on paediatric febrile neutropenia.

PURPOSE (STATING THE MAIN PURPOSES AND RESEARCH QUESTION): Many children have no significant sequelae of febrile neutropenia. A systematic review of clinical studies demonstrated patients at low risk of septic complications can be safely treated as outpatients using oral antibiotics with low rates of treatment failure. Introducing earlier discharge may improve quality of life, reduce hospital acquired infection and reduce healthcare service pressures. However, the review raised concerns that this might not be acceptable to patients, families and healthcare professionals. METHODS: This qualitative synthesis explored experiences of early discharge in paediatric febrile neutropenia, including reports from studies of adult febrile neutropenia and from other paediatric conditions. Systematic literature searching preceded meta-ethnographic analysis, including reading the studies and determining relationships between studies, translation of studies and synthesis of these translations. RESULTS: Nine papers were included. The overarching experience of early discharge is that decision-making is complex and difficult and influenced by fear, timing and resources. From this background, we identified two distinct themes. First, participants struggled with practical consequences of treatment regimens, namely childcare, finances and follow-up. A second theme identified social and emotional issues, including isolation, relational and environmental challenges. Linking these, participants considered continuity of care and the need for information important. CONCLUSIONS: Trust and confidence appeared interdependent with resources available to families-both are required to manage early discharge. Socially informed resilience is relevant to facilitating successful discharge strategies. Interventions which foster resilience may mediate the ability and inclination of families to accept early discharge. Services have an important role in recognising and enhancing resilience.

Survival rates and prognostic predictors of high grade brain stem gliomas in childhood: a systematic review and meta-analysis.

Diagnosis of a pediatric high grade brain stem glioma is devastating with dismal outcomes. This systematic review and meta-analysis was undertaken to determine the survival rates and assess potential prognostic factors including selected interventions. Studies included involved pediatric participants with high grade brain stem gliomas diagnosed by magnetic resonance imaging or biopsy reporting overall survival rates. Meta-analysis was undertaken using a binomial random effects model. Sixty-five studies (2336 participants) were included. Meta-analysis showed 1 year overall survival (OS) of 41% (95% confidence interval (CI) 38-44%, I-sq 52%, 2083 participants), 2 year OS of 15.3% (95% confidence interval 12-20%, I-sq 73.1%, 1329 participants) and 3 year OS of 7.3% (95% confidence interval 5.2-10%, I-sq 26%, 584 participants). Meta-analyses of median overall survival results was not possible due to the lack of reported measures of variance. Subgroup analysis comparing date of study, classification of tumor, use of temozolomide, non-standard interventions or phase 1/2 versus other studies demonstrated no difference in survival outcomes. There was insufficient data to undertake subgroup meta-analysis of patient age, duration of symptoms, K27M histone mutations and AVCR1 mutations. Survival outcomes of high grade brain stem gliomas have remained very poor, and do not clearly vary according to classification, phase of study or use of different therapeutic interventions. Future studies should harmonize outcome and prognostic variable reporting to enable accurate meta-analysis and better exploration of prognosis.

Videolaryngoscopy versus direct laryngoscopy for tracheal intubation in children (excluding neonates).

BACKGROUND: Direct laryngoscopy is the method currently used for tracheal intubation in children. It occasionally offers unexpectedly poor laryngeal views. Indirect laryngoscopy involves visualizing the vocal cords by means other than obtaining a direct sight, with the potential to improve outcomes. We reviewed the current available literature and performed a meta-analysis to compare direct versus indirect laryngoscopy, or videolaryngoscopy, with regards to efficacy and adverse effects. OBJECTIVES: To assess the efficacy of indirect laryngoscopy, or videolaryngoscopy, versus direct laryngoscopy for intubation of children with regards to intubation time, number of attempts at intubation, and adverse haemodynamic responses to endotracheal intubation. We also assessed other adverse responses to intubation, such as trauma to oral, pharyngeal, and laryngeal structures, and we assessed vocal cord view scores. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and trial registers (www.clinicaltrials.gov and www.controlledtrials) in November 2015. We reran the search in January 2017. We added new studies of potential interest to a list of 'Studies awaiting classification' and will incorporate them into formal review findings during the review update. We performed reference checking and citation searching and contacted the authors of unpublished data to ask for more information. We applied no language restrictions. SELECTION CRITERIA: We included only randomized controlled trials. Participants were children aged 28 days to 18 years. Investigators performed intubations using any type of indirect laryngoscopes, or videolaryngoscopes, versus direct laryngoscopes. DATA COLLECTION AND ANALYSIS: We used Cochrane standard methodological procedures. Two review authors independently reviewed titles, extracted data, and assessed risk of bias. MAIN RESULTS: We included 12 studies (803 children) in this review and meta-analysis. We identified three studies that are awaiting classification and two ongoing studies.Trial results show that a longer intubation time was required when indirect laryngoscopy, or videolaryngoscopy, was used instead of direct laryngoscopy (12 trials; n = 798; mean difference (MD) 5.49 seconds, 95% confidence interval (CI) 1.37 to 9.60; I2 = 90%; very low-quality evidence). Researchers found no significant differences between direct and indirect laryngoscopy on assessment of success of the first attempt at intubation (11 trials; n = 749; risk ratio (RR) 0.96, 95% CI 0.91 to 1.02; I2 = 67%; low-quality evidence) and observed that unsuccessful intubation (five trials; n = 263) was significantly increased in the indirect laryngoscopy, or videolaryngoscopy, group (RR 4.93, 95% CI 1.33 to 18.31; I2 = 0%; low-quality evidence). Five studies reported the effect of intubation on oxygen saturation (n = 272; very low-quality evidence). Five children had desaturation during intubation: one from the direct laryngoscopy group and four from the indirect laryngoscopy, or videolaryngoscopy, group.Two studies (n = 100) reported other haemodynamic responses to intubation (very low-quality evidence). One study reported a significant increase in heart rate five minutes after intubation in the indirect laryngoscopy group (P = 0.007); the other study found that the heart rate change in the direct laryngoscopy group was significantly less than the heart rate change in the indirect laryngoscopy, or videolaryngoscopy, group (P < 0.001). A total of five studies (n = 244; very low-quality evidence) looked at evidence of trauma resulting from intubation. Investigators reported that only two children from the direct laryngoscopy group had trauma compared with no children in the indirect laryngoscopy, or videolaryngoscopy, group.Use of indirect laryngoscopy, or videolaryngoscopy, improved the percentage of glottic opening (five trials; n = 256). Studies noted no significant difference in Cormack and Lehane score (C&L) grade 1 (three trials; n = 190; RR 1.06, 95% CI 0.93 to 1.21; I2 = 59%). AUTHORS' CONCLUSIONS: Evidence suggests that indirect laryngoscopy, or videolaryngoscopy, leads to prolonged intubation time with an increased rate of intubation failure when compared with direct laryngoscopy (very low-quality evidence due to imprecision, inconsistency, and study limitations). Review authors had difficulty reaching conclusions on adverse haemodynamic responses and other adverse effects of intubation, as only a few children were reported to have these outcomes. Use of indirect laryngoscopy, or videolaryngoscopy, might lead to improved vocal cord view, but marked heterogeneity between studies made it difficult for review authors to reach conclusions on this outcome.

Multi-Professional Perspectives on Adolescent and Young Adult Oncology Across Europe: An e-Delphi Survey.

The aims of this article are to describe the ongoing development of adolescent and young adult (AYA) cancer services within the European Union (EU), and to develop consensus on key areas within the field. This survey used an e-Delphi design. An initial survey was distributed via email to professionals working in Europe. A snowball sampling technique was used to promote distribution. Consensus was sought over three rounds from October 2012 to April 2015. Consensus was defined as >80% agreement ("agree" or "strongly agree"). Sixty professionals participated in round 1, 106 in round 2, and 61 in round 3. Twenty-six countries were represented across all rounds. Consensus was achieved for: the need for national policy guidance, the importance of patient choice, the validity of the International Charter of Rights for Young People, and some aspects of multi-disciplinary working. There was 75% agreement on a single definition of the patient age range within AYA cancer care. European professionals with expertise in AYA cancer care reached consensus on key elements of care for this group. The optimal AYA age range remained an elusive topic on which to agree. The broad engagement and interest in AYA cancer across the EU through the European Network for Cancer in Children and Adolescents (ENCCA) network was also demonstrated.

Critical review of current clinical practice guidelines for antifungal therapy in paediatric haematology and oncology.

PURPOSE: The incidence of invasive fungal disease (IFD) is rising, but its treatment in paediatric haematology and oncology patients is not yet standardised. This review aimed to critically appraise and analyse the clinical practice guidelines (CPGs) that are available for paediatric IFD. METHODS: Electronic searches of MEDLINE, MEDLINE in-Process & Other non-Indexed Citations, the Guidelines International Network (GIN), guideline.gov and Google were performed and combined fungal disease (Fung* OR antifung*OR Candida* OR Aspergill*) with prophylaxis or treatment (prophyl* OR therap* OR treatment). All guidelines were assessed using the AGREE II tool and recommendations relating to prophylaxis, empirical treatment and specific therapy were extracted. RESULTS: Nineteen guidelines met the inclusion criteria. The AGREE II scores for the rigour of development domain ranged from 11 to 92 % with a median of 53 % (interquartile range 32-69 %). Fluconazole was recommended as antifungal prophylaxis in all nine of the included guidelines which recommended a specific drug. Liposomal amphotericin B was recommended in all five guidelines giving empirical therapy recommendations. Specific therapy recommendations were given for oral or genital candidiasis, invasive candida infection, invasive aspergillosis and other mould infections. CONCLUSIONS: In many areas, recommendations were clear about appropriate practice but further clarity was required, particularly relating to the decision to discontinue empirical antifungal treatment, the relative benefits of empiric and pre-emptive strategies and risk stratification. Future CPGs could consider working to published guideline production methodologies and sharing summaries of evidence appraisal to reduce duplication of effort, improving the quality and efficiency of CPGs in this area.

Aminoaciduria in the prediction of ifosfamide-induced tubulopathy after childhood cancer: a feasibility study.

BACKGROUND: Ifosfamide, an alkylating agent used widely in the treatment of childhood malignancy, can cause many side effects including a proximal tubulopathy. Studies suggest that aminoaciduria is seen most commonly of all the biochemical abnormalities of ifosfamide-induced tubulopathy. A recent systematic review has found a paucity of data regarding the value of early markers indicating clinically significant tubulopathy. We undertook a pilot study to determine the feasibility of examining whether patients can be risk-stratified on the basis of aminoaciduria for the development of future significant ifosfamide-induced tubulopathy, to allow the evolution of appropriate follow-up strategies. We also aimed to define accrual rates, costs and clinical demands for a future larger study. METHODS: This observational study recruited 21 patients from the Leeds Paediatric Oncology service. The medical notes of each patient were reviewed for demographic and clinical data. Simultaneous samples of blood and urine were obtained. RESULTS: The investigations in the feasibility study were acceptable to patients and were minimally demanding on both clinical and laboratory staff. Financially, the cost per patient was minimal. This study was not powered to detect significant associations with TmP/GFR (ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate), growth and electrolyte supplementation. However, all patients with minimal aminoaciduria (≤2 elevated urinary amino acids) had normal TmP/GFR and no need for electrolyte supplementation. CONCLUSIONS: This pilot study has shown that a larger study is feasible and may provide clinically useful data to change current practice. This should aim to establish whether the number of abnormal amino acids or the degree of abnormality is most significant in predicting clinically significant proximal tubulopathy.