Building a collaborative cloud platform to accelerate heart, lung, blood, and sleep research.

Research increasingly relies on interrogating large-scale data resources. The NIH National Heart, Lung, and Blood Institute developed the NHLBI BioData CatalystⓇ (BDC), a community-driven ecosystem where researchers, including bench and clinical scientists, statisticians, and algorithm developers, find, access, share, store, and compute on large-scale datasets. This ecosystem provides secure, cloud-based workspaces, user authentication and authorization, search, tools and workflows, applications, and new innovative features to address community needs, including exploratory data analysis, genomic and imaging tools, tools for reproducibility, and improved interoperability with other NIH data science platforms. BDC offers straightforward access to large-scale datasets and computational resources that support precision medicine for heart, lung, blood, and sleep conditions, leveraging separately developed and managed platforms to maximize flexibility based on researcher needs, expertise, and backgrounds. Through the NHLBI BioData Catalyst Fellows Program, BDC facilitates scientific discoveries and technological advances. BDC also facilitated accelerated research on the coronavirus disease-2019 (COVID-19) pandemic.

Application of the matched nested case-control design to the secondary analysis of trial data.

BACKGROUND: A nested case-control study is an efficient design that can be embedded within an existing cohort study or randomised trial. It has a number of advantages compared to the conventional case-control design, and has the potential to answer important research questions using untapped prospectively collected data. METHODS: We demonstrate the utility of the matched nested case-control design by applying it to a secondary analysis of the Abnormal Doppler Enteral Prescription Trial. We investigated the role of milk feed type and changes in milk feed type in the development of necrotising enterocolitis in a group of 398 high risk growth-restricted preterm infants. RESULTS: Using matching, we were able to generate a comparable sample of controls selected from the same population as the cases. In contrast to the standard case-control design, exposure status was ascertained prior to the outcome event occurring and the comparison between the cases and matched controls could be made at the point at which the event occurred. This enabled us to reliably investigate the temporal relationship between feed type and necrotising enterocolitis. CONCLUSIONS: A matched nested case-control study can be used to identify credible associations in a secondary analysis of clinical trial data where the exposure of interest was not randomised, and has several advantages over a standard case-control design. This method offers the potential to make reliable inferences in scenarios where it would be unethical or impractical to perform a randomised clinical trial.

Economic evaluation alongside the Speed of Increasing milk Feeds Trial (SIFT).

OBJECTIVE: To evaluate the cost-effectiveness of two rates of enteral feed advancement (18 vs 30 mL/kg/day) in very preterm and very low birth weight infants. DESIGN: Within-trial economic evaluation alongside a multicentre, two-arm parallel group, randomised controlled trial (Speed of Increasing milk Feeds Trial). SETTING: 55 UK neonatal units from May 2013 to June 2015. PATIENTS: Infants born <32 weeks' gestation or <1500 g, receiving less than 30 mL/kg/day of milk at trial enrolment. Infants with a known severe congenital anomaly, no realistic chance of survival, or unlikely to be traceable for follow-up, were ineligible. INTERVENTIONS: When clinicians were ready to start advancing feed volumes, infants were randomised to receive daily increments in feed volume of 30 mL/kg (intervention) or 18 mL/kg (control). MAIN OUTCOME MEASURE: Cost per additional survivor without moderate to severe neurodevelopmental disability at 24 months of age corrected for prematurity. RESULTS: Average costs per infant were slightly higher for faster feeds compared with slower feeds (mean difference £267, 95% CI -6928 to 8117). Fewer infants achieved the principal outcome of survival without moderate to severe neurodevelopmental disability at 24 months in the faster feeds arm (802/1224 vs 848/1246). The stochastic cost-effectiveness analysis showed a likelihood of worse outcomes for faster feeds compared with slower feeds. CONCLUSIONS: The stochastic cost-effectiveness analysis shows faster feeds are broadly equivalent on cost grounds. However, in terms of outcomes at 24 months age (corrected for prematurity), faster feeds are harmful. Faster feeds should not be recommended on either cost or effectiveness grounds to achieve the primary outcome.

Two speeds of increasing milk feeds for very preterm or very low-birthweight infants: the SIFT RCT.

BACKGROUND: Observational data suggest that slowly advancing enteral feeds in preterm infants may reduce necrotising enterocolitis but increase late-onset sepsis. The Speed of Increasing milk Feeds Trial (SIFT) compared two rates of feed advancement. OBJECTIVE: To determine if faster (30 ml/kg/day) or slower (18 ml/kg/day) daily feed increments improve survival without moderate or severe disability and other morbidities in very preterm or very low-birthweight infants. DESIGN: This was a multicentre, two-arm, parallel-group, randomised controlled trial. Randomisation was via a web-hosted minimisation algorithm. It was not possible to safely and completely blind caregivers and parents. SETTING: The setting was 55 UK neonatal units, from May 2013 to June 2015. PARTICIPANTS: The participants were infants born at < 32 weeks' gestation or a weight of < 1500 g, who were receiving < 30 ml/kg/day of milk at trial enrolment. INTERVENTIONS: When clinicians were ready to start advancing feed volumes, the infant was randomised to receive daily feed increments of either 30 ml/kg/day or 18 ml/kg/day. In total, 1400 infants were allocated to fast feeds and 1404 infants were allocated to slow feeds. MAIN OUTCOME MEASURES: The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months of age, corrected for gestational age. The secondary outcomes were mortality; moderate or severe neurodevelopmental disability at 24 months corrected for gestational age; death before discharge home; microbiologically confirmed or clinically suspected late-onset sepsis; necrotising enterocolitis (Bell's stage 2 or 3); time taken to reach full milk feeds (tolerating 150 ml/kg/day for 3 consecutive days); growth from birth to discharge; duration of parenteral feeding; time in intensive care; duration of hospital stay; diagnosis of cerebral palsy by a doctor or other health professional; and individual components of the definition of moderate or severe neurodevelopmental disability. RESULTS: The results showed that survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 out of 1224 (65.5%) infants allocated to faster increments and 848 out of 1246 (68.1%) infants allocated to slower increments (adjusted risk ratio 0.96, 95% confidence interval 0.92 to 1.01). There was no significant difference between groups in the risk of the individual components of the primary outcome or in the important hospital outcomes: late-onset sepsis (adjusted risk ratio 0.96, 95% confidence interval 0.86 to 1.07) or necrotising enterocolitis (adjusted risk ratio 0.88, 95% confidence interval 0.68 to 1.16). Cost-consequence analysis showed that the faster feed increment rate was less costly but also less effective than the slower rate in terms of achieving the primary outcome, so was therefore found to not be cost-effective. Four unexpected serious adverse events were reported, two in each group. None was assessed as being causally related to the intervention. LIMITATIONS: The study could not be blinded, so care may have been affected by knowledge of allocation. Although well powered for comparisons of all infants, subgroup comparisons were underpowered. CONCLUSIONS: No clear advantage was identified for the important outcomes in very preterm or very low-birthweight infants when milk feeds were advanced in daily volume increments of 30 ml/kg/day or 18 ml/kg/day. In terms of future work, the interaction of different milk types with increments merits further examination, as may different increments in infants at the extremes of gestation or birthweight. TRIAL REGISTRATION: Current Controlled Trials ISRCTN76463425. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 18. See the NIHR Journals Library website for further project information.

Some infants who are born early need to be fed through a tube into their stomach. A small volume of milk is given to begin with, which is gradually increased. To determine whether infants do better if they are fed faster or slower, this study compared increasing the milk feeds by 30 ml/kg/day with increasing the milk feeds by 18 ml/kg/day, aiming to get to full feeds (when other fluids are not needed) in 5 or 9 days. We compared results from the two groups at discharge from hospital and at 24 months of age, after correcting for prematurity. We also assessed the economic impact of the two daily feed increments, interviewed parents about taking part in multiple studies and tested methods for improving questionnaire returns. The faster-fed group reached full milk feeds sooner and needed less intravenous nutrition, and the proportion of infants developing bowel inflammation or bloodstream infection were similar. At 24 months of age, we found an unexpected increase in the risk of moderate or severe motor impairment in the faster-fed group, which is difficult to explain. We also saw that other types of disability were more frequent in the faster group, although this was not significantly different mathematically. This means that no clear advantage of increasing feeds at faster or slower rates was identified and health professionals will need to carefully consider how to increase feeds. After accepting the increased risk of disability, an economic evaluation showed that increasing milk feed volumes at a faster rate was not a cost-effective strategy. Interviews with parents showed that they valued opportunities for their infant to take part in studies, but this interaction is complex and difficult to remember at a stressful and confusing time and made worse by considering multiple studies. More questionnaires were returned when vouchers were given before rather than after receiving them.

Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants.

BACKGROUND: Observational data have shown that slow advancement of enteral feeding volumes in preterm infants is associated with a reduced risk of necrotizing enterocolitis but an increased risk of late-onset sepsis. However, data from randomized trials are limited. METHODS: We randomly assigned very preterm or very-low-birth-weight infants to daily milk increments of 30 ml per kilogram of body weight (faster increment) or 18 ml per kilogram (slower increment) until reaching full feeding volumes. The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months. Secondary outcomes included components of the primary outcome, confirmed or suspected late-onset sepsis, necrotizing enterocolitis, and cerebral palsy. RESULTS: Among 2804 infants who underwent randomization, the primary outcome could be assessed in 1224 (87.4%) assigned to the faster increment and 1246 (88.7%) assigned to the slower increment. Survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 of 1224 infants (65.5%) assigned to the faster increment and 848 of 1246 (68.1%) assigned to the slower increment (adjusted risk ratio, 0.96; 95% confidence interval [CI], 0.92 to 1.01; P = 0.16). Late-onset sepsis occurred in 414 of 1389 infants (29.8%) in the faster-increment group and 434 of 1397 (31.1%) in the slower-increment group (adjusted risk ratio, 0.96; 95% CI, 0.86 to 1.07). Necrotizing enterocolitis occurred in 70 of 1394 infants (5.0%) in the faster-increment group and 78 of 1399 (5.6%) in the slower-increment group (adjusted risk ratio, 0.88; 95% CI, 0.68 to 1.16). CONCLUSIONS: There was no significant difference in survival without moderate or severe neurodevelopmental disability at 24 months in very preterm or very-low-birth-weight infants with a strategy of advancing milk feeding volumes in daily increments of 30 ml per kilogram as compared with 18 ml per kilogram. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; SIFT Current Controlled Trials number, ISRCTN76463425.).

Successfully implementing and embedding guidelines to improve the nutrition and growth of preterm infants in neonatal intensive care: a prospective interventional study.

OBJECTIVES: We aimed to improve the nutritional care of preterm infants by developing a complex (multifaceted) intervention intended to translate current evidence into practice. We used the sociological framework of Normalization Process Theory (NPT), to guide implementation in order to embed the new practices into routine care. DESIGN: A prospective interventional study with a before and after methodology. PARTICIPANTS: Infants <30 weeks gestation or <1500 g at birth. SETTING: Tertiary neonatal intensive care unit. INTERVENTIONS: The intervention was introduced in phases: phase A (control period, January-August 2011); phase B (partial implementation; improved parenteral and enteral nutrition solutions, nutrition team, education, August-December 2011); phase C (full implementation; guidelines, screening tool, 'nurse champions', January-December 2012); phase D (postimplementation; January-June 2013). Bimonthly audits and staff NPT questionnaires were used to measure guideline compliance and 'normalisation', respectively. NPT Scores were used to guide implementation in real time. Data on nutrient intakes and growth were collected continuously. RESULTS: There were 52, 36, 75 and 35 infants in phases A, B, C and D, respectively. Mean guideline compliance exceeded 75% throughout the intervention period, peaking at 85%. Guideline compliance and NPT scores both increased over time, (r=0.92 and 0.15, p<0.03 for both), with a significant linear association between the two (r=0.21, p<0.01). There were significant improvements in daily protein intake and weight gain between birth and discharge in phases B and Ccompared with phase A (p<0.01 for all), which were sustained into phase D. CONCLUSIONS: NPT and audit results suggest that the intervention was rapidly incorporated into practice, with high guideline compliance and accompanying improvements in protein intake and weight gain. NPT appears to offer an effective way of implementing new practices such that they lead to sustained changes in care. Complex interventions based on current evidence can improve both practice and clinical outcomes.

The Speed of Increasing milk Feeds: a randomised controlled trial.

BACKGROUND: In the UK, 1-2% of infants are born very preterm (<32 weeks of gestation) or have very low birth weight (<1500 g). Very preterm infants are initially unable to be fed nutritional volumes of milk and therefore require intravenous nutrition. Milk feeding strategies influence several long and short term health outcomes including growth, survival, infection (associated with intravenous nutrition) and necrotising enterocolitis (NEC); with both infection and NEC being key predictive factors of long term disability. Currently there is no consistent strategy for feeding preterm infants across the UK. The SIFT trial will test two speeds of increasing milk feeds with the primary aim of determining effects on survival without moderate or severe neurodevelopmental disability at 24 months of age, corrected for prematurity. The trial will also examine many secondary outcomes including infection, NEC, time taken to reach full feeds and growth. METHODS/DESIGN: Two thousand eight hundred very preterm or very low birth weight infants will be recruited from approximately 30 hospitals across the UK to a randomised controlled trial. Infants with severe congenital anomaly or no realistic chance of survival will be excluded. Infants will be randomly allocated to either a faster (30 ml/kg/day) or slower (18 ml/kg/day) rate of increase in milk feeds. Data will be collected during the neonatal hospital stay on weight, infection rates, episodes of NEC, length of stay and time to reach full milk feeds. Long term health outcomes comprising vision, hearing, motor and cognitive impairment will be assessed at 24 months of age (corrected for prematurity) using a parent report questionnaire. DISCUSSION: Extensive searches have found no active or proposed studies investigating the rate of increasing milk feeds. The results of this trial will have importance for optimising incremental milk feeding for very preterm and/or very low birth weight infants. No additional resources will be required to implement an optimal feeding strategy, and therefore if successful, the trial results could rapidly be adopted across the NHS at low cost. TRIAL REGISTRATION: ISRCTN Registry; ISRCTN76463425 on 5 March, 2013.

Nutrition and neurodevelopmental outcomes in preterm infants: a systematic review.

UNLABELLED: A systematic review with meta-analysis was carried out to investigate the effects of increased nutritional intake, via either macronutrient or multinutrient intervention, during the neonatal period on neurodevelopmental outcomes in infants born at <32 weeks of gestation or weighing <1501 g at birth. CONCLUSION: Although the relationship remains unclear, increased early nutrition may reduce neurodevelopmental impairment in this group of infants. Future research should focus on using standardised nutritional interventions and an agreed neurodevelopmental assessment battery.

Dopamine receptors reveal an essential role of IFT-B, KIF17, and Rab23 in delivering specific receptors to primary cilia.

Appropriate physiological signaling by primary cilia depends on the specific targeting of particular receptors to the ciliary membrane, but how this occurs remains poorly understood. In this study, we show that D1-type dopaminergic receptors are delivered to cilia from the extra-ciliary plasma membrane by a mechanism requiring the receptor cytoplasmic tail, the intraflagellar transport complex-B (IFT-B), and ciliary kinesin KIF17. This targeting mechanism critically depends on Rab23, a small guanine nucleotide binding protein that has important effects on physiological signaling from cilia but was not known previously to be essential for ciliary delivery of any cargo. Depleting Rab23 prevents dopamine receptors from accessing the ciliary membrane. Conversely, fusion of Rab23 to a non-ciliary receptor is sufficient to drive robust, nucleotide-dependent mis-localization to the ciliary membrane. Dopamine receptors thus reveal a previously unrecognized mechanism of ciliary receptor targeting and functional role of Rab23 in promoting this process.

How to use: nutritional assessment in neonates.

Adequate nutrition and growth during the neonatal period are important, especially for preterm infants, for whom there is evidence of poor nutrient intakes and growth, and this has important implications for their health in later life. Increased nutritional support while on the neonatal intensive care unit has been shown to improve growth, but such support is not universally available. Being able to carry out and interpret a nutritional assessment is therefore an important skill for paediatricians caring for neonates. This article aims to explain how to use nutritional assessment in neonates and provides some tools to make this process as straightforward as possible.

Vitamins--conventional uses and new insights.

There are 13 nutrients classified as vitamins: 4 'fat-soluble' and 9 'water-soluble'. All are essential to maintain healthy homeostasis and metabolic function. Preterm infants are born with low levels and reduced stores of fat-soluble vitamins. Active placental transfer of water-soluble vitamins ensures high levels at birth, but as they are not stored, levels fall rapidly. All VLBW and ELBW infants require vitamins to be provided soon after birth. Quantifying exact requirements of each vitamin which will meet the needs for all infants is difficult due to a limited evidence base. However, timely prescription of vitamin supplements and awareness of situations where delivery or uptake might be compromised will help to ensure that these vulnerable patients do not suffer from vitamin deficiencies. Multivitamin preparations are available for parenteral and enteral use. Vitamins A, C and E have important functions as antioxidants. Further research is required to understand optimal doses and routes of administration for initial and ongoing nutritional support.

Feeding infants below 29 weeks' gestation with abnormal antenatal Doppler: analysis from a randomised trial.

OBJECTIVE: To describe feeding and gastrointestinal outcomes in growth-restricted infants <29 weeks' gestation and to determine the rate of feed advancement which they tolerate. DESIGN: Analysis of prospectively collected data from a randomised feeding trial, the Abnormal Doppler Enteral Prescription Trial (ADEPT). SETTING: 54 neonatal units in the UK and Ireland. PARTICIPANTS: 404 preterm, growth-restricted infants with abnormal antenatal Doppler studies from ADEPT. 83 infants <29 weeks and 312 infants ≥ 29 weeks' gestation were included in this analysis. INTERVENTIONS: In ADEPT, infants were randomised to start milk 'early' on day 2 after birth, or 'late' on day 6. Subsequent feed advancement followed a regimen, which should have achieved full feeds by day 16 in the early and day 20 in the late group. MAIN OUTCOME MEASURES: Full feeds were achieved later in infants <29 weeks; median age 28 days {IQR 22-40} compared with 19 days {IQR 17-23} in infants ≥ 29 weeks (HR 0.35, 95% CI 0.3 to 0.5). The incidence of necrotising enterocolitis was also higher in this group; 32/83 (39%) compared to 32/312 (10%) in those ≥ 29 weeks (RR 3.7, 95% CI 2.4 to 5.7). Infants <29 weeks tolerated very little milk for the first 10 days of life and reached full feeds 9 days later than predicted from the trial regimen. CONCLUSIONS: Growth-restricted infants born <29 weeks' gestation with abnormal antenatal Doppler failed to tolerate even the careful feeding regimen of ADEPT. A slower advancement of feeds may be required for these infants. TRIAL REGISTRATION NUMBER: ISRCTN87351483.

Early parenteral nutrition and growth outcomes in preterm infants: a systematic review and meta-analysis.

BACKGROUND: The achievement of adequate nutritional intakes in preterm infants is challenging and may explain the poor growth often seen in this group. The use of early parenteral nutrition (PN) is one potential strategy to address this problem, although the benefits and harms are unknown. OBJECTIVE: We determined whether earlier administration of PN benefits growth outcomes in preterm infants. DESIGN: We conducted a systematic review of randomized controlled trials (RCTs) and observational studies. RESULTS: Eight RCTs and 13 observational studies met the inclusion criteria (n = 553 and 1796 infants). The meta-analysis was limited by disparate growth-outcome measures. An assessment of bias was difficult because of inadequate reporting. Results are given as mean differences (95% CIs). Early PN reduced the time to regain birth weight by 2.2 d (1.1, 3.2 d) for RCTs and 3.2 d (2.0, 4.4 d) in observational studies. The maximum percentage weight loss with early PN was lower by 3.1 percentage points (1.7, 4.5 percentage points) for RCTs and by 3.5 percentage points (2.6, 4.3 percentage points) for observational studies. Early PN improved weight at discharge or 36 wk postmenstrual age by 14.9 g (5.3, 24.5 g) (observational studies only), but no benefit was shown for length or head circumference. There was no evidence that early PN significantly affects risk of mortality, necrotizing enterocolitis, sepsis, chronic lung disease, intraventricular hemorrhage, or cholestasis. CONCLUSIONS: The results of this review, although subject to some limitations, show that early PN provides a benefit for some short-term growth outcomes. No evidence that early PN increases morbidity or mortality was found. Neonatal research would benefit from the development of a set of core growth outcome measures.

Milk osmolality: does it matter?

High osmolality of infant feed reflects a high concentration of solute particles and has been implicated as a cause of necrotising enterocolitis. Evidence for direct intestinal mucosal injury as a result of hyperosmolar feeds is scant, and no good evidence has been found to support such an association. High osmolality of enteral substrate may, however, slow down gastric emptying. Osmolality of current infant feeds ranges from around 300 mOsm/kg in human breast milk to just more than 400 mOsm/kg in fully fortified breast milk. Addition of mineral and vitamin supplements to small volumes of milk can increase osmolality significantly and should be avoided if possible.

Preterm birth and body composition at term equivalent age: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Infants born preterm are significantly lighter and shorter on reaching term equivalent age (TEA) than are those born at term, but the relation with body composition is less clear. We conducted a systematic review to assess the body composition at TEA of infants born preterm. METHODS: The databases MEDLINE, Embase, CINAHL, HMIC, "Web of Science," and "CSA Conference Papers Index" were searched between 1947 and June 2011, with selective citation and reference searching. Included studies had to have directly compared measures of body composition at TEA in preterm infants and infants born full-term. Data on body composition, anthropometry, and birth details were extracted from each article. RESULTS: Eight studies (733 infants) fulfilled the inclusion criteria. Mean gestational age and weight at birth were 30.0 weeks and 1.18 kg in the preterm group and 39.6 weeks and 3.41 kg in the term group, respectively. Meta-analysis showed that the preterm infants had a greater percentage total body fat at TEA than those born full-term (mean difference, 3%; P = .03), less fat mass (mean difference, 50 g; P = .03), and much less fat-free mass (mean difference, 460 g; P < .0001). CONCLUSIONS: The body composition at TEA of infants born preterm is different than that of infants born at term. Preterm infants have less lean tissue but more similar fat mass. There is a need to determine whether improved nutritional management can enhance lean tissue acquisition, which indicates a need for measures of body composition in addition to routine anthropometry.

Early or delayed enteral feeding for preterm growth-restricted infants: a randomized trial.

BACKGROUND: Growth-restricted preterm infants are at increased risk of developing necrotizing enterocolitis (NEC) and initiation of enteral feeding is frequently delayed. There is no evidence that this delay is beneficial and it might further compromise nutrition and growth. METHODS: Infants with gestation below 35 weeks, birth weight below the 10th centile, and abnormal antenatal umbilical artery Doppler waveforms were randomly allocated to commence enteral feeds "early," on day 2 after birth, or "late," on day 6. Gradual increase in feeds was guided by a "feeding prescription" with rate of increase the same for both groups. Primary outcomes were time to achieve full enteral feeding sustained for 72 hours and NEC. RESULTS: Four hundred four infants were randomly assigned from 54 hospitals in the United Kingdom and Ireland (202 to each group). Median gestation was 31 weeks. Full, sustained, enteral feeding was achieved at an earlier age in the early group: median age was 18 days compared with 21 days (hazard ratio: 1.36 [95% confidence interval: 1.11-1.67]). There was no evidence of a difference in the incidence of NEC: 18% in the early group and 15% in the late group (relative risk: 1.2 [95% confidence interval: 0.77-1.87]). Early feeding resulted in shorter duration of parenteral nutrition and high-dependency care, lower incidence of cholestatic jaundice, and improved SD score for weight at discharge. CONCLUSIONS: Early introduction of enteral feeds in growth-restricted preterm infants results in earlier achievement of full enteral feeding and does not appear to increase the risk of NEC.