Genotyping, sequencing and analysis of 140,000 adults from Mexico City.

The Mexico City Prospective Study is a prospective cohort of more than 150,000 adults recruited two decades ago from the urban districts of Coyoacán and Iztapalapa in Mexico City1. Here we generated genotype and exome-sequencing data for all individuals and whole-genome sequencing data for 9,950 selected individuals. We describe high levels of relatedness and substantial heterogeneity in ancestry composition across individuals. Most sequenced individuals had admixed Indigenous American, European and African ancestry, with extensive admixture from Indigenous populations in central, southern and southeastern Mexico. Indigenous Mexican segments of the genome had lower levels of coding variation but an excess of homozygous loss-of-function variants compared with segments of African and European origin. We estimated ancestry-specific allele frequencies at 142 million genomic variants, with an effective sample size of 91,856 for Indigenous Mexican ancestry at exome variants, all available through a public browser. Using whole-genome sequencing, we developed an imputation reference panel that outperforms existing panels at common variants in individuals with high proportions of central, southern and southeastern Indigenous Mexican ancestry. Our work illustrates the value of genetic studies in diverse populations and provides foundational imputation and allele frequency resources for future genetic studies in Mexico and in the United States, where the Hispanic/Latino population is predominantly of Mexican descent.

Impact of Colorectal Nurse Specialist supervised parental administration of rectal washouts on Hirschsprung's disease outcomes: a retrospective review.

PURPOSE: To highlight the utility of Colorectal Nurse Specialist (CNS) supervised parental administration of rectal washouts in the management of Hirschsprung's disease (HD). METHODS: Retrospective case note review of HD patients treated at a tertiary children's hospital in United Kingdom from January 2011 to December 2022. Data collected included demographics, complications, enterocolitis, obstructive symptoms and stomas. Primary pull-through (PT) is done 8-12 weeks after birth. Parental expertise in performing rectal washouts at home is ensured by our CNS team before and after PT. RESULTS: PT was completed in 69 of 74 HD patients. Rectal washouts were attempted on 63 patients before PT. Failure of rectal washout efficacy necessitated a stoma in four patients (6.4%). Of the 65 patients who had PT and stoma closed, three (4.5%) required a further stoma over a mean follow-up period of 57 months (Range 7-144 months). Two of these had intractable diarrhoea due to Total Colonic Aganglionosis (TCA). One patient (1.5%) had unmanageable obstructive symptoms requiring re-diversion. Hirschsprung-associated enterocolitis (HAEC) requiring hospital admission occurred in 14 patients (21%). CONCLUSION: Our stoma rates are lower compared to recent UK data. This could potentially be due to emphasis on parental ability to perform effective rectal washouts at home under CNS supervision.

Redeployment to critical care during the COVID-19 pandemic: A phenomenological study.

BACKGROUND: The redeployment of staff which involves moving staff from one clinical setting to another is a key feature of health care management. Rising demand associated with chronic disease and seasonal variation makes redeployment increasingly commonplace. During the COVID-19 pandemic preparation for the influx of patients included sourcing equipment and resources and the redeployment of staff to respiratory wards and critical care. AIM: The aim of this study was to explore the lived experience of redeployment to critical care during the COVID-19 pandemic from the perspective of those individuals who were moved to help and critical care core staff. STUDY DESIGN: A transcendental phenomenological study involving semi-structured interviews with staff redeployed and critical care core staff was conducted. Data were collected from staff in one critical care department of a large NHS Trust in England between the second and third pandemic wave (April-June 2021). RESULTS: Analysis of the data led to the identification of seven meaning units: intention, apprehension, expectations, familiarity, preparation, support, and own work. Intention related to the decisions made by managers regarding whom to redeploy and the reasons why people were chosen. Apprehension and expectations were closely linked and related to critical care skills and knowledge as well as anxiety about infection risk. Familiarity was a key element of people feeling comfortable and the confidence core staff had in colleagues who had come to help. Support and preparation helped but staff were anxious about their own work and concerned about the open-ended nature of redeployment. CONCLUSION: Familiarity and recency of critical care experience played a significant role in how useful redeployed staff were. Redeployed staff were concerned about assumptions being made and expectations of themselves as well as detachment from their usual support network. RELEVANCE TO CLINICAL PRACTICE: Continued shortages of registered nurses globally combined with the need to create additional critical care capacity during emergencies such as infection outbreaks means that redeployment of staff will continue for some time. Identifying the impact of redeployment on staff will enable services to better prepare and support registered nurses who are redeployed to critical care.

Embedding the A-EQUIP model of restorative supervision in a critical care unit by professional nurse advocates.

The professional nurse advocate (PNA) programme was launched in March 2021, which was towards the end of the third wave of COVID-19 and the start of a critical point of recovery. COVID-19 placed exceptional challenges and pressure on healthcare staff, with many experiencing feelings of stress and burnout. The role of the PNA emerged as a response to the impact this had upon the nursing workforce. PNAs are trained to facilitate restorative clinical supervision and to advocate education for quality improvement, resulting in improvements to patient care and staff wellbeing. The programme started with 400 critical care nurses; since then it has been rolled out to all specialties, with the aim to have 5000 PNAs integrated into the national workforce by April 2022. Criteria for the level 7 PNA training programme requires a registered nurse to be working in a patient-facing role, at band 5 or above, hold a level 6 qualification and have approval from their line manager. The training programme is typically 10 to 12 days in length over a 12-week period. This article explores the implementation of the PNA role in a critical care unit.

The effects of moral norms and anticipated guilt on COVID19 prevention behaviors.

Studies have shown that older adolescents have a low perceived personal risk of COVID-19, and yet their ability and willingness to engage in COVID-19 prevention behaviors is imperative for community health. Thus, health communication scholars need to consider alternative psycho-social predictors of prevention behaviors that will assist in protecting others in a pandemic. Based on Schwartz's Norms Activation Model (NAM; Schwartz, 1977), we examined the relationship between moral norms and COVID-19 prevention behaviors (mask wearing and physical distancing). We predicted that anticipated guilt would mediate the relationship between moral norms and intention to engage in prevention behaviors, and that collective orientation would strengthen the association between moral norms and anticipated guilt. We tested predictions with data from a cross-sectional survey with a probability-based sample of college students at a large land grant university. These data indicated that moral norms were associated with behavioral intention, and this relationship was mediated by anticipated guilt. Collective orientation was found to moderate the relationship between moral norms and anticipated guilt in the context of physical distancing but not mask wearing. These findings suggest that making moral norms salient when designing an intervention is an effective strategy for older adolescents. Supplementary information: The online version contains supplementary material available at 10.1007/s12144-023-04477-5.

General and Abdominal Adiposity and Mortality in Mexico City: A Prospective Study of 150 000 Adults.

Background: Some reports suggest that body mass index (BMI) is not strongly associated with mortality in Hispanic populations. Objective: To assess the causal relevance of adiposity to mortality in Mexican adults, avoiding reverse causality biases. Design: Prospective study. Setting: 2 Mexico City districts. Participants: 159 755 adults aged 35 years and older at recruitment, followed for up to 14 years. Participants with a hemoglobin A1c level of 7% or greater, diabetes, or other chronic diseases were excluded. Measurements: BMI, waist-to-hip ratio, waist circumference, and cause-specific mortality. Cox regression, adjusted for confounders, yielded mortality hazard ratios (HRs) after at least 5 years of follow-up and before age 75 years. Results: Among 115 400 participants aged 35 to <75 years at recruitment, mean BMI was 28.0 kg/m2 (SD, 4.1 kg/m2) in men and 29.6 kg/m2 (SD, 5.1 kg/m2) in women. The association of BMI at recruitment with all-cause mortality was J-shaped, with the minimum at 25 to <27.5 kg/m2. Above 25 kg/m2, each 5-kg/m2 increase in BMI was associated with a 30% increase in all-cause mortality (HR, 1.30 [95% CI, 1.24 to 1.36]). This association was stronger at ages 40 to <60 years (HR, 1.40 [CI, 1.30 to 1.49]) than at ages 60 to <75 years (HR, 1.24 [CI, 1.17 to 1.31]) but was not materially affected by sex, smoking, or other confounders. The associations of mortality with BMI and waist-to-hip ratio were similarly strong, and each was weakened only slightly by adjustment for the other. Waist circumference was strongly related to mortality and remained so even after adjustment for BMI and hip circumference. Limitation: Analyses were limited to mortality. Conclusion: General, and particularly abdominal, adiposity were strongly associated with mortality in this Mexican population. Primary Funding Source: Mexican Health Ministry, Mexican National Council of Science and Technology, Wellcome Trust, Medical Research Council, and Kidney Research UK.

The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years.

With 10+ years follow-up in the Leukaemia Research Fund (LRF) CLL4 trial, we report the effect of salvage therapy, and the clinical/biological features of the 10-year survivors treated for chronic lymphocytic leukaemia (CLL). Overall survival (OS) was similar in the three randomized arms. With fludarabine-plus-cyclophosphamide (FC), progression-free survival (PFS) was significantly longer (P < 0.0001), but OS after progression significantly shorter, than in the chlorambucil or fludarabine arms (P < 0.0001). 614/777 patients progressed; 524 received second-line and 260 third-line therapy, with significantly better complete remission (CR) rates compared to first-line in the chlorambucil arm (7% vs. 13% after second-, 18% after third-line), but worse in the FC arm (38% vs. 15% after both second and third-line). OS 10 years after progression was better after a second-line CR versus a partial response (36% vs. 16%) and better with FC-based second-line therapy (including rituximab in 20%) or a stem cell transplant (28%) versus all other treatments (10%, P < 0.0001). The 176 (24%) 10-year survivors tended to be aged <70 years, with a "good risk" prognostic profile, stage A-progressive, achieving at least one CR, with a first-line PFS >3 years and receiving ≤2 lines of treatment. In conclusion, clinical/biological features and salvage treatments both influence the long-term outcome. Second-line therapies that induce a CR can improve OS in CLL patients.

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.

Infection-related mortality in children with acute lymphoblastic leukemia: an analysis of infectious deaths on UKALL2003.

Although infection is the major cause of treatment-related mortality (TRM) in childhood acute lymphoblastic leukemia, factors associated with infection-related mortality (IRM) are poorly understood. To address this, we report an analysis of all 75 cases of IRM in the United Kingdom Childhood Acute Lymphoblastic Leukaemia Randomised Trial 2003 (UKALL 2003). The 5-year cumulative incidence of IRM was 2.4% (95% confidence interval [CI], 1.9%-3.0%), accounting for 75 (30%) of 249 trial deaths and 75 (64%) of 117 TRM deaths. Risk for IRM as a proportion of TRM was greater in induction than other phases (77% vs 56%; P = .02). Sixty-eight percent of cases were associated with bacterial infection (64% Gram-negative) and 20% with fungal infection. Down syndrome was the most significant risk factor for IRM (odds ratio [OR], 12.08; 95% CI, 6.54-22.32; P < .0001). In addition, there was a trend toward increased IRM in girls (OR, 1.63; 95% CI, 1.02-2.61; P = .04), as well as increasing treatment intensity (regimen B vs A: OR, 2.11 [95% CI, 1.24-3.60]; regimen C vs A: OR, 1.41 [95% CI, 0.76-2.62]; P = .02). Importantly, patients with Down syndrome were at significantly higher risk for IRM during maintenance (P = .048). Our results confirm Down syndrome as a major risk factor for IRM. Enhanced supportive care and prophylactic antibiotics should be considered in high-risk patient groups and during periods of increased risk. This study was registered at http://www.controlled-trials.com/ as #ISRCTN07355119.

A novel integrated cytogenetic and genomic classification refines risk stratification in pediatric acute lymphoblastic leukemia.

Recent genomic studies have provided a refined genetic map of acute lymphoblastic leukemia (ALL) and increased the number of potential prognostic markers. Therefore, we integrated copy-number alteration data from the 8 most commonly deleted genes, subordinately, with established chromosomal abnormalities to derive a 2-tier genetic classification. The classification was developed using 809 ALL97/99 patients and validated using 742 United Kingdom (UK)ALL2003 patients. Good-risk (GR) genetic features included ETV6-RUNX1, high hyperdiploidy, normal copy-number status for all 8 genes, isolated deletions affecting ETV6/PAX5/BTG1, and ETV6 deletions with a single additional deletion of BTG1/PAX5/CDKN2A/B. All other genetic features were classified as poor risk (PR). Three-quarters of UKALL2003 patients had a GR genetic profile and a significantly improved event-free survival (EFS) (94%) compared with patients with a PR genetic profile (79%). This difference was driven by a lower relapse rate (4% vs 17%), was seen across all patient subgroups, and was independent of other risk factors. Even genetic GR patients with minimal residual disease (>0.01%) at day 29 had an EFS in excess of 90%. In conclusion, the integration of genomic and cytogenetic data defines 2 subgroups with distinct responses to treatment and identifies a large subset of children suitable for treatment deintensification.

Thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics.

The impact of thiopurine methyltransferase (TPMT) genotype on thiopurine dose intensity, myelosuppression and treatment outcome was investigated in the United Kingdom childhood acute lymphoblastic leukaemia (ALL) trial ALL97. TPMT heterozygotes had significantly more frequent cytopenias and therefore required dose adjustments below target levels significantly more often than TPMT wild-type patients although the average dose range was similar for both genotypes. Event-free survival (EFS) for patients heterozygous for the more common TPMT*1/*3A variant allele (n = 99, 5-year EFS 88%) was better than for both wild-type TPMT*1/*1 (n = 1206, EFS 80%, P = 0·05) and TPMT*1/*3C patients (n = 17, EFS 53%, P = 0·002); outcomes supported by a multivariate Cox regression analysis. Poor compliance without subsequent clinician intervention was associated with a worse EFS (P = 0·02) and such non-compliance may have contributed to the poorer outcome for TPMT*1/*3C patients. Patients prescribed escalated doses had a worse EFS (P = 0·04), but there was no difference in EFS by dose intensity or duration of cytopenias. In contrast to reports from some USA and Nordic trials, TPMT heterozygosity was not associated with a higher rate of second cancers. In conclusion, TPMT*1/*3A heterozygotes had a better EFS than TPMT wild-type patients. Thiopurine induced cytopenias were not detrimental to treatment outcome.

Thiopurine methyltransferase and treatment outcome in the UK acute lymphoblastic leukaemia trial ALL2003.

The influence of thiopurine methyltransferase (TPMT) genotype on treatment outcome was investigated in the United Kingdom childhood acute lymphoblastic leukaemia trial ALL2003, a trial in which treatment intensity was adjusted based on minimal residual disease (MRD). TPMT genotype was measured in 2387 patients (76% of trial entrants): 2190 were homozygous wild-type, 189 were heterozygous for low activity TPMT alleles (166 TPMT*1/*3A, 19 TPMT*1/*3C, 3 TPMT*1/*2 and 1 TPMT*1/*9) and 8 were TPMT deficient. In contrast to the preceding trial ALL97, there was no difference in event-free survival (EFS) between the TPMT genotypes. The 5-year EFS for heterozygous TPMT*1/*3A patients was the same in both trials (88%), but for the homozygous wild-type TPMT*1/*1 patients, EFS improved from 80% in ALL97% to 88% in ALL2003. Importantly, the unexplained worse outcome for heterozygous TPMT*1/*3C patients observed in ALL97 (5-year EFS 53%) was not seen in ALL2003 (5-year EFS 94%). In a multivariate Cox regression analysis the only significant factor affecting EFS was MRD status (hazard ratio for high-risk MRD patients 4·22, 95% confidence interval 2·97-5·99, P < 0·0001). In conclusion, refinements in risk stratification and treatment have reduced the influence of TPMT genotype on treatment outcome in a contemporary protocol.

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.

Outcome of Down syndrome associated acute lymphoblastic leukaemia treated on a contemporary protocol.

We report the outcome for children and young people with Down syndrome-associated acute lymphoblastic leukaemia (DS-ALL) treated on a contemporary protocol. Compared with non-DS ALL, patients with DS-ALL had an inferior event-free survival (65·6% vs. 87·7% at 5 years; P < 0·00005) and overall survival (70·0% vs. 92·2%; P < 0·00005). Excess treatment-related mortality - was primarily responsible for the worse outcomes for DS-ALL (21·6% at 5 years, vs. 3·3%, P < 0·00005). Minimal residual disease (MRD) risk status was highly discriminant for relapse in DS patients with 0/28 relapses in the MRD low risk group.

Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia.

We performed a meta-analysis of 3 genome-wide association studies to identify additional common variants influencing chronic lymphocytic leukemia (CLL) risk. The discovery phase was composed of genome-wide association study data from 1121 cases and 3745 controls. Replication analysis was performed in 861 cases and 2033 controls. We identified a novel CLL risk locus at 6p21.33 (rs210142; intronic to the BAK1 gene, BCL2 antagonist killer 1; P = 9.47 × 10(-16)). A strong relationship between risk genotype and reduced BAK1 expression was shown in lymphoblastoid cell lines. This finding provides additional support for polygenic inheritance to CLL and provides further insight into the biologic basis of disease development.

The clinical significance of patients' sex in chronic lymphocytic leukemia.

We examined the prognostic influence of gender in chronic lymphocytic leukemia. Data from four randomized trials (involving 1821 patients) and three registration studies of stage-A disease (involving 1299 patients) were analyzed. Overall survival at 10 years was better for women than men in all trials (27% versus 15%; P=0.0001) and in the registration series (55% versus 43%; P<0.0001). More women than men in the trials were Binet stage A-progressive (26% versus 15%), but gender was an independent predictor of survival in multivariate analysis of clinical variables (P<0.0001). Women responded better to treatment (overall response 83%) than men (71%; P<0.0001), within each stage and age group, although fewer women than men received the full treatment dose (79% versus 85%; P=0.01). Women were more likely than men to experience toxicity (85% versus 78%, P=0.01), particularly gastro-intestinal toxicity (57% versus 42%, P<0.0001). Laboratory markers in the LRF CLL4 trial showed a significantly lower incidence in women than men of unmutated IGHV genes, raised beta-2 microglobulin, CD38 and Zap-70 positivity and TP53 deletions/mutations and/or 11q deletions. We also highlight the higher male:female ratios in randomized trials versus studies of early chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis. Chronic lymphocytic leukemia in women runs a more benign clinical course than in men. Gender was also an independent predictor of response, suggesting that pharmacokinetic differences between the sexes and a possible effect of estrogens may contribute to the better outcome. Understanding the reasons for the different outcome by gender may improve patients' management. (LRF CLL4 controlled-trials.com identifier: ISRCTN58585610).

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.

Effect of Fenofibrate on Progression of Diabetic Retinopathy.

BACKGROUND: Findings from cardiovascular outcome trials suggest that fenofibrate therapy may reduce the progression of diabetic retinopathy. METHODS: We recruited and followed adults with nonreferable diabetic retinopathy or maculopathy using the national Diabetic Eye Screening (DES) program in Scotland. We randomly assigned participants to receive 145-mg fenofibrate tablets or placebo (taken daily or, in those with impaired renal function, on alternate days). The primary outcome was a composite of developing referable diabetic retinopathy or maculopathy (based on Scotland's DES grading scheme) or treatment (intravitreal injection, retinal laser, vitrectomy) for retinopathy or maculopathy. RESULTS: A total of 1151 participants were randomly assigned to treatment. During a median of 4.0 years, progression to referable diabetic retinopathy or maculopathy, or treatment thereof, occurred in 131 (22.7%) of 576 participants in the fenofibrate group and 168 (29.2%) of 575 in the placebo group (hazard ratio, 0.73; 95% confidence interval [CI], 0.58 to 0.91; P=0.006). In the fenofibrate group compared with the placebo group, the frequencies for any progression of retinopathy or maculopathy were 185 (32.1%) vs. 231 (40.2%); hazard ratio, 0.74; 95% CI, 0.61 to 0.90 and for the development of macular edema were 22 (3.8%) vs. 43 (7.5%); hazard ratio, 0.50; 95% CI, 0.30 to 0.84. Seventeen (3.0%) participants assigned fenofibrate and 28 (4.9%) assigned placebo were given treatment for retinopathy (hazard ratio, 0.58; 95% CI, 0.31 to 1.06). There was no effect on visual function, quality of life, or visual acuity. Trial-averaged estimated glomerular filtration rate was 7.9 (95% CI, 6.8 to 9.1) ml/min/1.73 m2 lower in participants in the fenofibrate group compared with the placebo group. Serious adverse events occurred in 208 (36.1%) participants allocated fenofibrate and 204 (35.5%) participants allocated placebo. CONCLUSIONS: Fenofibrate reduced progression of diabetic retinopathy compared with placebo among participants with early retinal changes. (Funded by the National Institute for Health and Care Research; ClinicalTrials.gov number, NCT03439345; ISRCTN number, ISRCTN15073006.).