SummaryBackgroundInfections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice.MethodsIn this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002.FindingsWe recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention.InterpretationEnteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants.FundingUK National Institute for Health Research Health Technology Assessment programme (10/57/49).

Allogeneic hematopoietic cell transplantation (HCT) is associated with significant morbidity and mortality, making advance care planning (ACP) and management especially important in this patient population. A paucity of data exists on the utilization of ACP among allogeneic HCT recipients and the relationship between ACP and intensity of healthcare utilization in these patients. We performed a retrospective review of patients receiving allogeneic HCT at our institution from 2008 to 2015 who had subsequently died after HCT. Documentation and timing of advance directive (AD) completion were abstracted from the electronic medical record. Outcomes of interest included use of intensive care unit (ICU) level of care at any time point after HCT, within 30 days of death, and within 14 days of death; use of mechanical ventilation at any time after HCT; and location of death. Univariate logistic regression was performed to explore associations between AD completion and each outcome. Of the 1031 patients who received allogeneic HCT during the study period, 422 decedents (41%) were included in the analysis. Forty-four percent had AD documentation prior to death. Most patients (69%) indicated that if terminally ill, they did not wish to be subjected to life-prolonging treatment attempts. Race/ethnicity was significantly associated with AD documentation, with non-Hispanic white patients documenting ADs more frequently (51%) compared with Hispanic (22%) or Asian patients (35%; P = .0007). Patients with ADs were less likely to use the ICU during the transplant course (41% for patients with ADs versus 52% of patients without ADs; P = .03) and also were less likely to receive mechanical ventilation at any point after transplantation (21% versus 37%, P < .001). AD documentation was also associated with decreased ICU use at the end of life; relative to patients without ADs, patients with ADs were more likely to die at home or in hospital as opposed to in the ICU (odds ratio, .44; 95% confidence interval, .27 to .72). ACP remains underused in allogeneic HCT. Adoption of a systematic practice to standardize AD documentation as part of allogeneic HCT planning has the potential to significantly reduce ICU use and mechanical ventilation while improving quality of care at end of life in HCT recipients.

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SUMMARY In prescribing a diabetic diet more attention has traditionally been paid to the amount of dietary carbohydrate than to its type or structure. We have compared the effect on blood glucose of substituting unrefined, whole foods for refined, processed foods in liberal carbohydrate diets (50-55%/ of dietary energy) eaten by 10 diabetic children in a randomised crossover study. All measurements were made at home. The unrefined diet used whole foods (including dried beans) supplying 60 g/day of dietary fibre. The refined diet used processed foods supplying 20 g/day of dietary fibre. Diets were isocaloric for carbohydrate, fat, and protein. Glycaemic control was assessed by daily urine analysis for glucose, home blood glucose measurements, glycosylated haemoglobin, and by a 24-hour profile of blood and urinary glucose carried out at home after 6 weeks on each diet. Glycaemic control was significantly better on the unrefined diet. On profile days mean blood glucose levels on the unrefined and refined diets respectively were: preprandial: 5 * 5 and 8 4 mmol/l; postprandial 8 5 and 12-2 mmol/l. The mean 24-hour urinary glucose excretion on the unrefined diet was 9 3 g and on the refined diet was 38-0 g. Six months after the study the children were eating appreciably more dietary fibre than before (mean increase 13 * 6 g/day). Attention to food type and structure can improve blood glucose control in diabetic children and should provide an acceptable and more rational basis for dietary prescription than one based on carbohydrate quantity alone.Traditional diabetic diets have paid more attention to the amount of dietary carbohydrate than to its structure or type. There is however a substantial amount of evidence to suggest that changing the physical form of the food in the diet,'2 and increasing

Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow’s milk, prevents infections and associated complications. Objective To determine whether or not enteral supplementation with bovine lactoferrin (The Tatua Cooperative Dairy Company Ltd, Morrinsville, New Zealand) reduces the risk of late-onset infection (acquired > 72 hours after birth) and other morbidity and mortality in very preterm infants. Design Randomised, placebo-controlled, parallel-group trial. Randomisation was via a web-based portal and used an algorithm that minimised for recruitment site, weeks of gestation, sex and single versus multiple births. Setting UK neonatal units between May 2014 and September 2017. Participants Infants born at < 32 weeks’ gestation and aged < 72 hours at trial enrolment. Interventions Eligible infants were allocated individually (1 : 1 ratio) to receive enteral bovine lactoferrin (150 mg/kg/day; maximum 300 mg/day) or sucrose (British Sugar, Peterborough, UK) placebo (same dose) once daily from trial entry until a postmenstrual age of 34 weeks. Parents, caregivers and outcome assessors were unaware of group assignment. Outcomes Primary outcome – microbiologically confirmed or clinically suspected late-onset infection. Secondary outcomes – microbiologically confirmed infection; all-cause mortality; severe necrotising enterocolitis (NEC); retinopathy of prematurity (ROP); bronchopulmonary dysplasia (BPD); a composite of infection, NEC, ROP, BPD and mortality; days of receipt of antimicrobials until 34 weeks’ postmenstrual age; length of stay in hospital; and length of stay in intensive care, high-dependency and special-care settings. Results Of 2203 enrolled infants, primary outcome data were available for 2182 infants (99%). In the intervention group, 316 out of 1093 (28.9%) infants acquired a late-onset infection versus 334 out of 1089 (30.7%) infants in the control group [adjusted risk ratio (RR) 0.95, 95% confidence interval (CI) 0.86 to 1.04]. There were no significant differences in any secondary outcomes: microbiologically confirmed infection (RR 1.05, 99% CI 0.87 to 1.26), mortality (RR 1.05, 99% CI 0.66 to 1.68), NEC (RR 1.13, 99% CI 0.68 to 1.89), ROP (RR 0.89, 99% CI 0.62 to 1.28), BPD (RR 1.01, 99% CI 0.90 to 1.13), or a composite of infection, NEC, ROP, BPD and mortality (RR 1.01, 99% CI 0.94 to 1.08). There were no differences in the number of days of receipt of antimicrobials, length of stay in hospital, or length of stay in intensive care, high-dependency or special-care settings. There were 16 reports of serious adverse events for infants in the lactoferrin group and 10 for infants in the sucrose group. Conclusions Enteral supplementation with bovine lactoferrin does not reduce the incidence of infection, mortality or other morbidity in very preterm infants. Future work Increase the precision of the estimates of effect on rarer secondary outcomes by combining the data in a meta-analysis with data from other trials. A mechanistic study is being conducted in a subgroup of trial participants to explore whether or not lactoferrin supplementation affects the intestinal microbiome and metabolite profile of very preterm infants. Trial registration Current Controlled Trials ISRCTN88261002. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 74. See the NIHR Journals Library website for further project information. This trial was also sponsored by the University of Oxford, Oxford, UK. The funder provided advice and support and monitored study progress but did not have a role in study design or data collection, analysis and interpretation.