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Paediatric trials must contend with many challenges that adult trials face but often bring additional obstacles. Decentralised trials, where some or all trial methods occur away from a centralised location, are a promising strategy to help meet these challenges. This scoping review aims to (a) identify what methods and tools have been used to create and conduct entirely online-decentralised trials with children and (b) determine the gaps in the knowledge in this field. This review will describe the methods used in these trials to identify their facilitators and the gaps in the knowledge. The methods were informed by guidance from the Joanna Briggs Institute and the PRISMA extension for scoping reviews. We systematically searched MEDLINE, CENTRAL, CINAHL, and Embase databases, trial registries, pre-print servers, and the internet. We included randomised and quasi-randomised trials conducted entirely online with participants under 18 published in English. A risk of bias assessment was completed for all included studies. Twenty-one trials met our inclusion criteria. The average age of participants was 14.6 years. Social media was the most common method of online recruitment. Most trials employed an external host website to store and protect their data. Duration of trials ranged from single-session interventions up to ten weeks. Fourteen trials compensated participants. Eight trials involved children in their trial design process; none reported compensation for this. Most trials had a low risk of bias in \"random sequence generation\", \"selective reporting\", and \"other\". Most trials had a high risk of bias in \"blinding participants and personnel\", \"blinding of outcome assessment\", and \"incomplete outcome data\". \"Allocation concealment\" was unclear in most studies. There was a lack of transparent reporting of the recruitment, randomisation, and retention methods used in many of the trials included in this review. Patient and public involvement (PPI) was not common, and the compensation of PPI partners was not reported in any study. Consent methods and protection against fraudulent entries to trials were creative and thoroughly discussed by some trials and not addressed by others. More work and thorough reporting of how these trials are conducted is needed to increase their reproducibility and quality. Ethical approval was not necessary since all data sources used are publicly available.

Health research increasingly incorporates public and patient involvement (PPI) to enhance trial inclusivity and relevance, and it is often mandated by funding and regulatory bodies. PPI boosts public engagement with trials and aligns trial objectives more closely with the priorities of the groups they aim to benefit. The Kid’s Trial, an online randomised trial co-created with children, aims to help them better understand what randomised trials are, why they matter, and improve their critical thinking skills. To ensure inclusivity and relevance, we established two PPI groups: the Children’s Research Advisory Group (CRAG) and the Parents’ Research Advisory Group (PRAG). We recruited a representative sample of children and parents from diverse ethnic, geographic, and socioeconomic backgrounds to reflect the trial’s target demographic. We engaged PPI group members through social media and email campaigns aimed at parents of children aged 7 to 12. PPI meetings were conducted online, followed set agendas, and included real-time trial updates, post-meeting feedback surveys, and polls. A PPI compensation plan was established in advance. Online interviews later captured their insights and experiences as PPI partners. Seven family units, comprised of eight children and seven parents, were recruited over 15 weeks from six countries. PPI partners shaped the trial design by contributing to website animations, aesthetic changes, and language adaptations. Interviews were analysed using reflexive thematic analysis to explore the facilitators, challenges, and outcomes of participating in our online research advisory groups. Reflections from researchers and PPI partners demonstrated that participation in the advisory groups enhanced children’s learning and confidence. Many members, including children and adults, experienced unexpected positive outcomes, such as increased scientific literacy, science communication and confidence. Their involvement meaningfully shaped the trial’s development and processes. This study also provides guidance for researchers engaging similar demographics in future PPI activities. Plain English summary Health research now often includes input from the public and patients (Patient and Public Involvement or PPI) to make studies more inclusive and useful. Many funding and regulatory organisations require this. When the public is involved, research studies become more relevant to the people they aim to help. The Kid’s Trial is an online study designed with children to teach them how health research works and help them think critically about health information they encounter. To make sure The Kid’s Trial was inclusive and meaningful, we created two PPI groups made up of children and their parents to help us design it. We used social media and email to recruit a diverse group of children and parents from different backgrounds. These groups met online to discuss the trial, make improvements, and give feedback. They worked on the website, website animations, trial design, and the language we used. The PPI group members were compensated for their time. Seven family units, consisting of eight children and seven parents from six countries, joined the PPI groups. We interviewed group members to understand what worked well, what was challenging, and what they gained from participating in the PPI groups. Children felt that their confidence and learning had improved. Many PPI group members experienced unexpected benefits. Their input significantly influenced the design of The Kid’s Trial. This study also offers valuable advice for researchers seeking to include children and parents as PPI partners in future studies.

Background Paediatric trials must contend with many challenges that adult trials face but often bring additional obstacles. Decentralised trials, where some or all trial methods occur away from a centralised location, are a promising strategy to help meet these challenges. This scoping review aims to (a) identify what methods and tools have been used to create and conduct entirely online-decentralised trials with children and (b) determine the gaps in the knowledge in this field. This review will describe the methods used in these trials to identify their facilitators and the gaps in the knowledge. Methods The methods were informed by guidance from the Joanna Briggs Institute and the PRISMA extension for scoping reviews. We systematically searched MEDLINE, CENTRAL, CINAHL, and Embase databases, trial registries, pre-print servers, and the internet. We included randomised and quasi-randomised trials conducted entirely online with participants under 18 published in English. A risk of bias assessment was completed for all included studies. Results Twenty-one trials met our inclusion criteria. The average age of participants was 14.6 years. Social media was the most common method of online recruitment. Most trials employed an external host website to store and protect their data. Duration of trials ranged from single-session interventions up to ten weeks. Fourteen trials compensated participants. Eight trials involved children in their trial design process; none reported compensation for this. Most trials had a low risk of bias in “random sequence generation”, “selective reporting”, and “other”. Most trials had a high risk of bias in “blinding participants and personnel”, “blinding of outcome assessment”, and “incomplete outcome data”. “Allocation concealment” was unclear in most studies. Conclusions There was a lack of transparent reporting of the recruitment, randomisation, and retention methods used in many of the trials included in this review. Patient and public involvement (PPI) was not common, and the compensation of PPI partners was not reported in any study. Consent methods and protection against fraudulent entries to trials were creative and thoroughly discussed by some trials and not addressed by others. More work and thorough reporting of how these trials are conducted is needed to increase their reproducibility and quality. Ethics and dissemination Ethical approval was not necessary since all data sources used are publicly available.

TP53 and FGFR3 mutations are the most common mutations in bladder cancers. FGFR3 mutations are most frequent in low-grade low-stage tumours, whereas TP53 mutations are most frequent in high-grade high-stage tumours. Several studies have reported FGFR3 and TP53 mutations to be mutually exclusive events, whereas others have reported them to be independent. We carried out a meta-analysis of published findings for FGFR3 and TP53 mutations in bladder cancer (535 tumours, 6 publications) and additional unpublished data for 382 tumours. TP53 and FGFR3 mutations were not independent events for all tumours considered together (OR = 0.25 [0.18-0.37], p = 0.0001) or for pT1 tumours alone (OR = 0.47 [0.28-0.79], p = 0.0009). However, if the analysis was restricted to pTa tumours or to muscle-invasive tumours alone, FGFR3 and TP53 mutations were independent events (OR = 0.56 [0.23-1.36] (p = 0.12) and OR = 0.99 [0.37-2.7] (p = 0.35), respectively). After stratification of the tumours by stage and grade, no dependence was detected in the five tumour groups considered (pTaG1 and pTaG2 together, pTaG3, pT1G2, pT1G3, pT2-4). These differences in findings can be attributed to the putative existence of two different pathways of tumour progression in bladder cancer: the CIS pathway, in which FGFR3 mutations are rare, and the Ta pathway, in which FGFR3 mutations are frequent. TP53 mutations occur at the earliest stage of the CIS pathway, whereas they occur would much later in the Ta pathway, at the T1G3 or muscle-invasive stage.

Transforming growth factor type β (TGF-β) is a multifunctional factor that regulates proliferation and differentiation of many cell types. TGF-β mediates its effects by binding to and activating cell surface receptors that possess serine/threonine kinase activity. However, the intracellular signaling pathways through which TGF-β receptors act remain largely unknown. Here we show that TGF-β activates a 78-kDa protein (p78) serine/threonine kinase as evidenced by an in-gel kinase assay. Ligand-induced activation of the kinase was near-maximal 5 min after TGF-β addition to the cells and occurred exclusively on serine and threonine residues. This kinase is distinct from TGF-β receptor type II, as well as several cytoplasmic serine/threonine kinases of similar size, including protein kinase C, Raf, mitogen-activated protein kinase kinase kinase, and ribosomal S6 kinase. Indeed, these kinases can be separated almost completely from p78 kinase by immunoprecipitation with specific antibodies. Furthermore, using different cell lines, we demonstrate that p78 kinase is activated only in cells for which TGF-β can act as a growth inhibitory factor. These data raise the interesting possibility that protein serine/threonine kinases contribute to the intracellular relay of biological signals originating from receptor serine/threonine kinases such as the TGF-β receptors.

Summary Background The effects on long-term outcome in childhood acute lymphoblastic leukaemia (ALL) of the duration and the intensity of maintenance chemotherapy need to be assessed reliably. With this objective the Childhood ALL Collaborative Group coordinated a worldwide overview of all randomised trials that began before 1987. Methods Individual patient data were sought for about 3900 children in trials of longer vs shorter maintenance (eg, 3 vs 2 years), 3700 in trials of intensive \"reinduction\" chemotherapy during maintenance, and 4400 in trials of various other questions, including 1300 in trials of pulses of vincristine and prednisone (VP) during maintenance. Analyses were of survival in first remission, overall survival, and cause-specific mortality. Findings Deaths during remission were increased by longer maintenance (2·7% vs 1·2%), VP pulses (4·0 vs 3·2%), and intensive reinduction (4·8% vs 3·3%), but these increases were counterbalanced by reductions in relapses. Total events (relapse or death) were significantly reduced by longer maintenance (23·3% vs 27·6%), VP pulses (31·2% vs40·4%) and intensive reinduction (27·8% vs 35·8%) (each 2p<0·001). Many of those who relapsed were successfully re-treated, however, and only for intensive reinduction was overall survival significantly improved (18·5% vs 22·3%; 2p=0·01). Interpretation Intensive reinduction chemotherapy in these trials produced an absolute improvement of about 4% in long-term survival; if the extra deaths in remission had been avoided, this would have been a 5% benefit. Further improvements in survival seem more likely to be obtained with intensive treatment than with longer low-level maintenance.

We calculate the contribution to the muon anomalous magnetic moment hadronic vacuum polarization from {the} connected diagrams of up and down quarks, omitting electromagnetism. We employ QCD gauge-field configurations with dynamical \\(u\\), \\(d\\), \\(s\\), and \\(c\\) quarks and the physical pion mass, and analyze five ensembles with lattice spacings ranging from \\(a \\approx 0.06\\) to~0.15~fm. The up- and down-quark masses in our simulations have equal masses \\(m_l\\). We obtain, in this world where all pions have the mass of the \\(\\pi^0\\), \\(10^{10} a_\\mu^{ll}({\\rm conn.}) = 637.8\\,(8.8)\\), in agreement with independent lattice-QCD calculations. We then combine this value with published lattice-QCD results for the connected contributions from strange, charm, and bottom quarks, and an estimate of the uncertainty due to the fact that our calculation does not include strong-isospin breaking, electromagnetism, or contributions from quark-disconnected diagrams. Our final result for the total \\(\\mathcal{O}(\\alpha^2)\\) hadronic vacuum polarization to the muon's anomalous magnetic moment is~\\(10^{10}a_\\mu^{\\rm HVP,LO} = 699(15)_{u,d}(1)_{s,c,b}\\), where the errors are from the light-quark and heavy-quark contributions, respectively. Our result agrees with both {\\it ab-initio} lattice-QCD calculations and phenomenological determinations from experimental \\(e^+e^-\\)-scattering data. It is \\(1.3\\sigma\\) below the \"no new physics\" value of the hadronic-vacuum-polarization contribution inferred from combining the BNL E821 measurement of \\(a_\\mu\\) with theoretical calculations of the other contributions.

We present results for the dominant light-quark connected contribution to the long-distance window (LD) of the hadronic vacuum polarization contribution (HVP) to the muon \\(g-2\\) from lattice quantum chromodynamics (QCD). Specifically, with a new determination of the lattice scale on MILC's physical-mass HISQ ensembles, using the \\(\\Omega^-\\) baryon mass, we obtain a result of \\(400.2(2.3)_{\\mathrm{stat}}(3.7)_{\\mathrm{syst}}[4.3]_{\\mathrm{total}} \\times 10^{-10}\\). Summing this result with our recent determinations of the light-quark connected contributions to the short- (SD) and intermediate-distance (W) windows, we obtain a sub-percent precision determination of the light-quark-connected contribution to HVP of \\(655.5(2.3)_{\\mathrm{stat}}(3.9)_{\\mathrm{syst}}[4.5]_{\\mathrm{total}} \\times 10^{-10}\\). Finally, as a consistency check, we verify that an independent analysis of the full contribution is in agreement with the sum of individual windows. We discuss our future plans for improvements of our HVP calculations to meet the target precision of the Fermilab \\(g-2\\) experiment.

We present complete results for the hadronic vacuum polarization (HVP) contribution to the muon anomalous magnetic moment \\(a_\\mu\\) in the short- and intermediate-distance window regions, which account for roughly 10% and 35% of the total HVP contribution to \\(a_\\mu\\), respectively. In particular, we perform lattice-QCD calculations for the isospin-symmetric connected and disconnected contributions, as well as corrections due to strong isospin-breaking. For the short-distance window observables, we investigate the so-called log-enhancement effects as well as the significant oscillations associated with staggered quarks in this region. For the dominant, isospin-symmetric light-quark connected contribution, we obtain \\(a^{ll,\\,{\\mathrm{SD}}}_{\\mu}(\\mathrm{conn.}) = 48.139(11)_{\\mathrm{stat}}(91)_{\\mathrm{syst}}[92]_{\\mathrm{total}} \\times 10^{-10}\\) and \\(a^{ll,\\,{\\mathrm{W}}}_{\\mu}(\\mathrm{conn.}) = 206.90(14)_{\\mathrm{stat}}(61)_{\\mathrm{syst}}[63]_{\\mathrm{total}} \\times 10^{-10}\\). We use Bayesian model averaging to fully estimate the covariance matrix between the individual contributions. Our determinations of the complete window contributions are \\(a^{{\\mathrm{SD}}}_{\\mu} = 69.05(1)_{\\mathrm{stat}}(21)_{\\mathrm{syst}}[21]_{\\mathrm{total}} \\times 10^{-10}\\) and \\(a^{{\\mathrm{W}}}_{\\mu} = 236.45(17)_{\\mathrm{stat}}(83)_{\\mathrm{syst}}[85]_{\\mathrm{total}} \\times 10^{-10}\\). This work is part of our ongoing effort to compute all contributions to HVP with an overall uncertainty at the few permille level.

All lattice-QCD calculations of the hadronic-vacuum-polarization contribution to the muon's anomalous magnetic moment to-date have been performed with degenerate up- and down-quark masses. Here we calculate directly the strong-isospin-breaking correction to \\(a_\\mu^{\\rm HVP}\\) for the first time with physical values of \\(m_u\\) and \\(m_d\\) and dynamical \\(u\\), \\(d\\), \\(s\\), and \\(c\\) quarks, thereby removing this important source of systematic uncertainty. We obtain a relative shift to be applied to lattice-QCD results obtained with degenerate light-quark masses of \\(\\delta a_\\mu^{{\\rm HVP,} m_u \\neq m_d}\\)= +1.5(7)%, in agreement with estimates from phenomenology and a recent lattice-QCD calculation with unphysically heavy pions.