Geolocator-tracking seabird migration and moult reveal large-scale, temperature-driven isoscapes in the NE Atlantic.

RATIONALE: By combining precision satellite-tracking with blood sampling, seabirds can be used to validate marine carbon and nitrogen isoscapes, but it is unclear whether a comparable approach using low-precision light-level geolocators (GLS) and feather sampling can be similarly effective. METHODS: Here we used GLS to identify wintering areas of northern gannets (Morus bassanus) and sampled winter grown feathers (confirmed from image analysis of non-breeding birds) to test for spatial gradients in δ13 C and δ15 N in the NE Atlantic. RESULTS: By matching winter-grown feathers with the non-breeding location of tracked birds we found latitudinal gradients in δ13 C and δ15 N in neritic waters. Moreover, isotopic patterns were best explained by sea surface temperature. Similar isotope gradients were found in fish muscle sampled at local ports. CONCLUSIONS: Our study reveals the potential of using seabird GLS and feathers to reconstruct large-scale isotopic patterns.

Action slips in food choices: A measure of habits and goal-directed control.

We report a new, simple instrumental action-slip task, which sets goal-directed action against putative S-R associations. On each training trial, participants were presented with one of two stimuli (blue or green coloured screen). One stimulus (S1) signalled that one joystick response (R1-left or right push) would earn one of two rewards (O1-jellybeans or Pringles points). A second stimulus (S2) signalled a different instrumental relationship (S2:R2-O2). On each test trial, participants were told which outcome could be earnt (O1/O2) on that trial. They were required to withhold responding until the screen changed colour to S1 or S2. On congruent test trials, the stimulus presented (e.g., S1) was associated with the same response (R1) as the outcome available on that trial (O1). On incongruent test trials, in contrast, the outcome (e.g., O1) preceded a stimulus that was associated with a different response (e.g., S2). Hence, in order to obtain the outcome (O1) on incongruent trials, participants were required to suppress any tendency they might have to make the response associated with the stimulus (R2 in response to S2). In two experiments, participants made more errors on incongruent than congruent trials. This result suggests that, on incongruent trials, the stimulus drove responding (e.g., S2 increased R2 responding) in a manner that was inconsistent with goal-directed action (e.g., R1 responding to obtain O1)-an action slip. The results are discussed in terms of popular dual-process theories of instrumental action and a single-process alternative.

Pre-testing effects are target-specific and are not driven by a generalised state of curiosity.

Guessing an answer to an unfamiliar question prior to seeing the answer leads to better memory than studying alone (the pre-testing effect), which some theories attribute to increased curiosity. A similar effect occurs in general knowledge learning: people are more likely to recall information that they were initially curious to learn. Gruber and Ranganath [(2019). How curiosity enhances hippocampus-dependent memory: The prediction, appraisal, curiosity, and exploration (PACE) framework. Trends in Cognitive Sciences, 23(12), 1014-1025] argued that unanswered questions can cause a state of curiosity during which encoding is enhanced for the missing answer, but also for incidental information presented at the time. If pre-testing similarly induces curiosity, then it too should produce better memory for incidental information. We tested this idea in three experiments that varied the order, nature and timing of the incidental material presented within a pre-testing context. All three experiments demonstrated a reliable pre-testing effect for the targets, but no benefit for the incidental material presented before the target. This pattern suggests that the pre-testing effect is highly specific and is not consistent with a generalised state of curiosity.

The benefits of impossible tests: Assessing the role of error-correction in the pretesting effect.

Relative to studying alone, guessing the meanings of unknown words can improve later recognition of their meanings, even if those guesses were incorrect - the pretesting effect (PTE). The error-correction hypothesis suggests that incorrect guesses produce error signals that promote memory for the meanings when they are revealed. The current research sought to test the error-correction explanation of the PTE. In three experiments, participants studied unfamiliar Finnish-English word pairs by either studying each complete pair or by guessing the English translation before its presentation. In the latter case, the participants also guessed which of two categories the word belonged to. Hence, guesses from the correct category were semantically closer to the true translation than guesses from the incorrect category. In Experiment 1, guessing increased subsequent recognition of the English translations, especially for translations that were presented on trials in which the participants' guesses were from the correct category. Experiment 2 replicated these target recognition effects while also demonstrating that they do not extend to associative recognition performance. Experiment 3 again replicated the target recognition pattern, while also examining participants' metacognitive recognition judgments. Participants correctly judged that their memory would be better after small than after large errors, but incorrectly believed that making any errors would be detrimental, relative to study-only. Overall, the data are inconsistent with the error-correction hypothesis; small, within-category errors produced better recognition than large, cross-category errors. Alternative theories, based on elaborative encoding and motivated learning, are considered.

Whole-genome characterization of chemoresistant ovarian cancer.

Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.

Human appetitive Pavlovian-to-instrumental transfer: a goal-directed account.

Pavlovian-to-instrumental transfer (PIT) tasks assess the impact of environmental stimuli on instrumental actions. Since their initial translation from animal to human experiments, PIT tasks have provided insight into the mechanisms that underlie reward-based behaviour. This review first examines the main types of PIT tasks used in humans. We then seek to contribute to the current debate as to whether human PIT effects reflect a controlled, goal-directed process, or a more automatic, non-goal-directed mechanism. We argue that the data favour a goal-directed process. The extent to which the major theories of PIT can account for these data is then explored. We discuss a number of associative accounts of PIT as well as dual-process versions of these theories. Ultimately, however, we favour a propositional account, in which human PIT effects are suggested to be driven by both perceived outcome availability and outcome value. In the final section of the review, we present the potential objections to the propositional approach that we anticipate from advocates of associative link theories and our response to them. We also identify areas for future research.

Pretesting boosts item but not source memory.

Two experiments examined the effect of pretesting on target recognition and source memory. In an initial encoding phase, participants attempted to learn the common English definitions of rare English words. For each rare word, the participants either guessed the definition of the rare English word before it was revealed (Pretest condition) or just studied the complete word pair without first guessing the definition (Read-only condition). To manipulate source information, the targets were either presented in different colours (Experiment 1) or lists (Experiment 2). In both experiments, the participants correctly recognised more targets from Pretest trials than Read-only trials, but showed no difference in source memory. Pretesting, therefore, appears to improve target recognition memory, but not memory for contextual information. The results are discussed in relation to semantic and episodic theories of the pretesting effect.

Response of triploid Atlantic salmon (Salmo salar) to commercial vaccines.

While triploid Atlantic salmon represent a practical and affordable solution to the issues associated with sexual maturation in the salmonid aquaculture industry, empirical evidence suggests triploids are more susceptible to disease and vaccine side-effects than diploids. With vaccination now part of routine husbandry, it is essential their response be studied to confirm their suitability for commercial production. This study tested the response of triploid and diploid Atlantic salmon to vaccination with commercially available vaccines. Triploid and diploid Atlantic salmon siblings were injected with one of three commercial vaccines (or sham-vaccinated) and monitored for performance throughout a commercial production cycle. Sampling at smolt and harvest was undertaken along with individual weight and length assessments through the cycle. Antibody response to Aeromonas salmonicida vaccination was similar in both ploidy, with a positive response in vaccine-injected fish. For both adhesions and melanin, analysis found that higher scores were more likely to occur as the anticipated severity of the vaccine increased. In addition, for adhesion scores at smolt and melanin scores at smolt and harvest, triploids were statistically more likely to exhibit high scores than diploids. Triploids maintained a significantly higher body weight during freshwater and until 11 months post-seawater transfer, with diploids weighing significantly more at harvest. Growth, represented by thermal growth coefficient (TGC), decreased in both ploidy as the severity of adhesions increased, and regression patterns did not differ significantly between ploidy. Vertebral deformity prevalence was consistently higher in triploids (smolt 12.3 ± 4.5%; harvest 34.9 ± 5.9%) than diploids (smolt 0.8 ± 0.5%; harvest 15.9 ± 1.9%), with no significant difference between vaccine groups in each ploidy. This study demonstrates that triploids respond as well to vaccination as diploids and provides further supporting evidence of triploid robustness for commercial aquaculture.

Selective effects of errorful generation on recognition memory: the role of motivation and surprise.

The current research examined the effects of errorful generation on memory, focusing particularly on the roles of motivation and surprise. In two experiments, participants were first presented with photographs of faces and were asked to associate four facts with each photograph. On Generate trials, the participants guessed two of the facts (Guess targets) before those correct facts, and another two correct facts (Study targets), were revealed. On the remaining Read trials, all four facts were presented without a guessing stage. In Experiment 1, participants also ranked their motivation to know the answers before they were revealed, or their surprise on learning the true answers. Guess targets were subsequently better recognised than the concurrently presented, non-guessed Study targets. Guess targets were also better recognised than Read targets, and recognition of Study and Read targets did not differ. Errorful generation also increased self-reported motivation, but not surprise. Experiment 2 showed that the results of Experiment 1 can outlive a 20-minute delay, and that they generalise to a more challenging recognition test. Together, the results suggest that errorful generation improves memory specifically for the guessed fact, and this may be linked to an increase in motivation to learn that fact.

Relapse in teenage and young adult patients treated on a paediatric minimal residual disease stratified ALL treatment protocol is associated with a poor outcome: results from UKALL2003.

Outcomes for teenage and young adult (TYA) patients with acute lymphoblastic leukaemia (ALL) who relapse on contemporary risk-adapted paediatric protocols are largely unknown and there is no consensus on optimal salvage strategies. We assessed the treatment and outcome of TYA patients (aged 16-24 years) recruited to the UKALL2003 trial, who relapsed following attainment of complete morphological remission. Forty-two of 223 patients (18·8%) relapsed, the majority (n = 26, 62%) on treatment. Thirty-eight (90%) patients received salvage treatment, with 22 (58%) achieving second remission (CR2) and 21 patients receiving an allogeneic haematopoietic cell transplant (alloHSCT). Post-relapse outcomes were poor with a 5-year overall survival (OS) of 23% (95% confidence interval; 11-37%). Outcomes for patients relapsing on active treatment were inferior to those relapsing after completing treatment (5-year OS 9% vs. 52%, log-rank P = 0·001). No patient with B cell ALL relapsing on treatment was alive at the end of the study period. TYA patients with ALL who relapse on the UK paediatric protocol, UKALL2003, are largely unsalvageable with conventional approaches aimed at achieving CR2 followed by alloHSCT. Future efforts should be aimed at identifying those patients who are destined to relapse and exploring novel treatment approaches for this high-risk group and for those who do relapse.

Efficacy and toxicity of a paediatric protocol in teenagers and young adults with Philadelphia chromosome negative acute lymphoblastic leukaemia: results from UKALL 2003.

Despite the substantial outcome improvements achieved in paediatric acute lymphoblastic leukaemia (ALL), survival in teenage and young adult (TYA) patients has remained inferior. We report the treatment outcomes and toxicity profiles observed in TYA patients treated on the UK paediatric ALL trial, UKALL2003. UKALL2003 was a multi-centre, prospective, randomized phase III trial, investigating treatment intensification or de-escalation according to minimal residual disease (MRD) kinetics at the end of induction. Of 3126 patients recruited to UKALL2003, 229 (7·3%) were aged 16-24 years. These patients were significantly more likely to have high risk MRD compared to 10-15 year olds (47·9% vs. 36·6%, P = 0·004). Nonetheless, 5-year event-free survival for the TYA cohort (aged 16-24 years) was 72·3% [95% confidence interval (CI): 66·2-78·4] overall and 92·6% (95% CI: 85·5-99·7) for MRD low risk patients. The risk of serious adverse events was higher in patients aged ≥10 years compared to those aged 9 or younger (P < 0·0001) and novel age-specific patterns of treatment-related toxicity were observed. TYA patients obtain excellent outcomes with a risk- and response-adapted paediatric chemotherapy protocol. Whilst those aged 10 years and older have excess toxicity compared with younger patients, the age association is specific to individual toxicities.

Improved Phytophthora resistance in commercial chickpea (Cicer arietinum) varieties negatively impacts symbiotic gene signalling and symbiotic potential in some varieties.

Breeding disease-resistant varieties is one of the most effective and economical means to combat soilborne diseases in pulse crops. Commonalities between pathogenic and mutualistic microbe colonization strategies, however, raises the concern that reduced susceptibility to pathogens may simultaneously reduce colonization by beneficial microbes. We investigate here the degree of overlap in the transcriptional response of the Phytophthora medicaginis susceptible chickpea variety 'Sonali' to the early colonization stages of either Phytophthora, rhizobial bacteria or arbuscular mycorrhizal fungi. From a total of 6476 genes differentially expressed in Sonali roots during colonization by any of the microbes tested, 10.2% were regulated in a similar manner regardless of whether it was the pathogenic oomycete or a mutualistic microbe colonizing the roots. Of these genes, 49.7% were oppositely regulated under the same conditions in the moderately Phytophthora resistant chickpea variety 'PBA HatTrick'. Chickpea varieties with improved resistance to Phytophthora also displayed lower colonization by rhizobial bacteria and mycorrhizal fungi leading to an increased reliance on N and P from soil. Together, our results suggest that marker-based breeding in crops such as chickpea should be further investigated such that plant disease resistance can be tailored to a specific pathogen without affecting mutualistic plant:microbe interactions.

Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial.

BACKGROUND: No randomised study has shown whether stratification of treatment by minimal residual disease (MRD) response improves outcome in children and young people with acute lymphoblastic leukaemia (ALL). We assessed whether children and young people with clinical standard and intermediate-risk ALL who have persistent MRD at the end of induction therapy benefit from augmented post-remission therapy. METHODS: Between Oct 1, 2003, and June 30, 2011, we enrolled eligible patients aged 1-24 years and initially categorised them into clinical standard-risk, intermediate-risk, and high-risk groups on the basis of a combination of National Cancer Institute criteria, cytogenetics, and early morphological response to induction therapy. Clinical standard-risk and intermediate-risk patients with MRD of 0·01% or higher at day 29 of induction (MRD high risk) were randomly assigned (1:1) to standard therapy (treatment regimens A and B) or augmented post-remission therapy (regimen C). Compared with standard therapy, the augmented treatment regimen (regimen C) included an additional eight doses of pegylated asparaginase, 18 doses of vincristine, and escalated-dose intravenous methotrexate without folinic acid rescue during interim maintenance courses. Computer randomisation was used for treatment allocation and was balanced for sex, age (<10 years vs ≥10 years), and white blood cell count at diagnosis (<50 × 10(9)/L vs ≥50 × 10(9)/L) by minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcomes were event-free survival and overall survival. Analyses were by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN07355119. FINDINGS: 533 MRD high-risk patients were randomly assigned to receive standard (n=266) or augmented (n=267) post-remission therapy. After a median follow-up of 70 months (IQR 52-91), 5-year event-free survival was better in the augmented treatment group (89·6% [95% CI 85·9-93·3]) than in the standard group (82·8% [78·1-87·5]; odds ratio [OR] 0·61 [95% CI 0·39-0·98], p=0·04). Overall survival at 5 years was numerically, but not significantly, higher in the augmented treatment group (92·9% [95% CI 89·8-96·0]) than in the standard therapy group (88·9% [85·0-92·8]; OR 0·67 [95% CI 0·38-1·17], p=0·16). More adverse events occurred in the augmented treatment group than in the standard group (asparaginase-related hypersensitivity in 18 [6·7%] in the augmented group vs two [0·8%] in the standard group and asparaginase-related pancreatitis in eight [3·0%] vs one [0·4%]; intravenous methotrexate-related mucositis in 11 [4·1%] vs three [1·1%] and methotrexate-related stomatitis in 48 [18·0%] vs 12 [4·5%]). INTERPRETATION: Our findings suggest that children and young people with acute lymphoblastic leukaemia and 0·01% or more MRD at the end of remission induction therapy could benefit from augmented post-remission therapy. However, the asparaginase and intravenous methotrexate used in the augmented treatment regimen is associated with more adverse events than is the standard post-remission treatment regimen. FUNDING: Medical Research Council and Leukaemia and Lymphoma Research.

Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003.

We investigated the outcome for children and young people with Early T-precursor acute lymphoblastic leukaemia (ETP-ALL), a recently described poor prognosis sub-group of T-ALL, treated on a contemporary protocol, UKALL 2003. After a median follow-up of 4 years and 10 months, the ETP sub-group, representing 16% of T-ALL patients, had non-significantly inferior 5-year event-free survival (76·7% vs. 84·6%, P = 0·2) and overall survival (82·4% vs. 90·9%, P = 0·1), and a higher relapse rate (18·6% vs. 9·6%, P = 0·1) compared to typical T-ALL. ETP-ALL has an intermediate risk outcome, which does not warrant experimental treatment or first remission allogeneic transplant for the group universally.

Evidence that the LRRK2 ROC domain Parkinson's disease-associated mutants A1442P and R1441C exhibit increased intracellular degradation.

Mutations in the leucine-rich repeat kinase 2 (lrrk2) gene are the leading genetic cause of Parkinson's disease (PD). In characterizing the novel ROC domain mutant A1442P, we compared its steady-state protein levels, propensity to aggregate, and toxicity with the pathogenic R1441C mutant and wild-type (WT) LRRK2. Mutant (R1441C and A1442P) and WT LRRK2 fused to green fluorescent protein (GFP) and FLAG were transiently expressed in HEK293 cells using plasmid constructs. Western analysis and fluorescence microscopy consistently demonstrated lower mutant LRRK2 protein levels compared with WT. A time-course expression study using flow cytometry showed that WT LRRK2 expression increased initially but then plateaued by 72 hr. Conversely, R1441C and A1442P mutant expression attained 85% and 74% of WT levels at 24 hr but fell to 68% and 55% of WT levels by 72 hr, respectively. We found that proteasome inhibition markedly increased mutant LRRK2 to levels approaching those of WT. Taken together, our findings reveal increased intracellular degradation for both mutants. Furthermore, the impact of mutant and WT LRRK2 expression on HEK293 cell viability was assessed under normative and oxidative (hydrogen peroxide) conditions and found not to differ. Expression of WT and mutant LRRK2 protein gave rise to intracellular aggregates of similar appearance and cellular localization. In summary, we provide evidence that the novel A1442P mutant and the previously investigated R1441C pathogenic mutant exhibit increased intracellular degradation, a property reportedly demonstrated for the pathogenic LRRK2 kinase domain mutant I2020T.

The eCollaborative: using a quality improvement collaborative to implement the National eHealth Record System in Australian primary care practices.

QUALITY PROBLEM: The new national patient-controlled electronic health record is an important quality improvement, and there was a pressing need to pilot its use in Australian primary care practices. Implementation of electronic health records in other countries has met with mixed success. INITIAL ASSESSMENT: New work was required in general practices participating in the national electronic health record. National implementers needed to engage with small private general practices to test the changes before general introduction. CHOICE OF SOLUTION: The National E-health Transition Authority contracted the Improvement Foundation Australia to conduct a quality improvement collaborative based on 9 years of experience with the Australian Primary Care Collaborative Program. IMPLEMENTATION: Aims, measures and change ideas were addressed in a collaborative programme of workshops and supported activity periods. Data quality measures and numbers of health summaries uploaded were collected monthly. Challenges such as the delay in implementation of the electronic health summary were met. EVALUATION: Fifty-six practices participated. Nine hundred and twenty-nine patients registered to participate, and 650 shared health summaries were uploaded. Five hundred and nineteen patient views occurred. Four hundred and twenty-one plan/do/study/act cycles were submitted by participating practices. LESSONS LEARNED: The collaborative methodology was adapted for implementing innovation and proved useful for engaging with multiple small practices, facilitating low-risk testing of processes, sharing ideas among participants, development of clinical champions and development of resources to support wider use. Email discussion between participants and system designers facilitated improvements. Data quality was a key challenge for this innovation, and quality measures chosen require development. Patient participants were partners in improvement.

The necessity of pharmacological prophylaxis against venous thromboembolism in major joint arthroplasty.

PURPOSE: Venous thromboembolism (VTE) is a recognised post-operative complication of major lower limb joint arthroplasty. Current National Institute for Health and Clinical Excellence (NICE) guidelines suggest the use of both mechanical and pharmacological prophylaxis following hip and knee replacement. Since the introduction of enhanced recovery programmes following hip and knee arthroplasty the requirement for routine pharmacological VTE prophylaxis has been questioned. The purpose of this study was to assess the efficacy of pharmacological prophylaxis against symptomatic VTE in patients undergoing hip and knee arthroplasty under an enhanced recovery programme. METHODS: Symptomatic VTE incidence was audited in 1,100 patients undergoing primary or revision total hip or knee arthroplasty at the same hospital with only mechanical prophylaxis from 2007 to 2009. Following addition of chemical prophylaxis (enoxaparin) symptomatic VTE incidence in 522 patients undergoing primary or revision total hip or knee arthroplasty from 2011 to 2012 was re-audited. RESULTS: In the mechanical prophylaxis group incidence of DVT was 0.73 % [95 % confidence interval (CI) 0.37-1.43 %] and incidence of pulmonary embolism (PE) 0.91 % (95 % CI 0.49-1.67 %). Following addition of pharmacological prophylaxis incidence of DVT was 0.57 % (95 % CI 0.20-1.68 %) and incidence of PE 1.15 % (95 % CI 0.53-2.48 %). CONCLUSIONS: We found no statistically significant difference in symptomatic VTE incidence following the addition of enoxaparin. We question whether routine pharmacological prophylaxis still has a role following total hip and knee arthroplasty. Peri-operative optimisation, including post-operative analgesia and mobility, with current enhanced recovery programmes may be sufficient. As anticoagulants carry increased risk of post-operative bleeding and wound ooze, in addition to significant cost implications, their role remains controversial.

Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial.

BACKGROUND: Minimal residual disease (MRD) is the most sensitive and specific predictor of relapse risk in children with acute lymphoblastic leukaemia (ALL) during remission. We assessed whether treatment intensity could be adjusted for children and young adults according to MRD risk stratification. METHODS: Between Oct 1, 2003 and June 30, 2011, consecutive children and young adults (aged 1-25 years) with ALL from the UK and Ireland were recruited. Eligible patients were categorised into clinical standard, intermediate, and high risk groups on the basis of a combination of National Cancer Institute (NCI) criteria, cytogenetics, and early response to induction therapy, which was assessed by bone marrow blast counts taken at days 8 (NCI high-risk patients) and 15 (NCI standard-risk patients) after induction began. Clinical standard-risk and intermediate-risk patients were assessed for MRD. Those classified as MRD low risk (undetectable MRD at the end of induction [day 29] or detectable MRD at day 29 that became undetectable by week 11) were randomly assigned to receive one or two delayed intensification courses. Patients had received induction, consolidation, and interim maintenance therapy before they began delayed intensification. Delayed intensification consisted of pegylated asparaginase on day 4; vincristine, dexamethasone (alternate weeks), and doxorubicin for 3 weeks; and 4 weeks of cyclophosphamide and cytarabine. Computer randomisation was done with stratification by MRD result and balancing for sex, age, and white blood cell count at diagnosis by method of minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcome was event-free survival (EFS), which was defined as time to relapse, secondary tumour, or death. Our aim was to rule out a 7% reduction in EFS in the group given one delayed intensification course relative to that given two delayed intensification courses. Analyses were by intention to treat. This trial is registered, number ISRCTN07355119. FINDINGS: Of 3207 patients registered in the trial overall, 521 MRD low-risk patients were randomly assigned to receive one (n=260) or two (n=261) delayed intensification courses. Median follow-up of these patients was 57 months (IQR 42-72). We recorded no significant difference in EFS between the group given one delayed intensification (94·4% at 5 years, 95% CI 91·1-97·7) and that given two delayed intensifications (95·5%, 92·8-98·2; unadjusted odds ratio 1·00, 95% CI 0·43-2·31; two-sided p=0·99). The difference in 5-year EFS between the two groups was 1·1% (95% CI -5·6 to 2·5). 11 patients (actuarial relapse at 5 years 5·6%, 95% CI 2·3-8·9) given one delayed intensification and six (2·4%, 0·2-4·6) given two delayed intensifications relapsed (p=0·23). Three patients (1·2%, 0-2·6) given two delayed intensifications died of treatment-related causes compared with none in the group given one delayed intensification (p=0·08). We recorded no significant difference between groups for serious adverse events and grade 3 or 4 toxic effects; however, the second delayed intensification course was associated with one (<1%) treatment-related death, and 74 episodes of grade 3 or 4 toxic effects in 45 patients (17%). INTERPRETATION: Treatment reduction is feasible for children and young adults with ALL who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD by the end of induction therapy. FUNDING: Medical Research Council and Leukaemia and Lymphoma Research.