ELFIN, the United Kingdom preterm lactoferrin trial: interpretation and future questions

2020 ◽  
Author(s):  
Janet Elizabeth Berrington ◽  
William McGuire ◽  
NIcholas David Embleton
Keyword(s):  
United Kingdom ◽  
Preterm Infants ◽  
Late Onset ◽  
Disease Onset ◽  
Intervention Group ◽  
Control Group ◽  
Bovine Lactoferrin ◽  
The United Kingdom ◽  
Late Onset Sepsis ◽  
The Uk

Previous studies suggested that supplemental bovine lactoferrin (BLF) given to preterm infants (<32 weeks gestation) may reduce late onset sepsis (LOS) and necrotising enterocolitis (NEC), but have been underpowered. The Enteral Lactoferrin in Neonates (ELFIN) study, performed in the United Kingdom (UK), aimed to further address this issue with a well powered double blinded placebo controlled trial of >2200 preterm infants. ELFIN did not demonstrate a reduction in LOS or NEC, or several other clinically important measures. 316 (29%) of 1093 infants in the intervention group developed late-onset sepsis versus 334 (31%) of 1089 in the control group with an adjusted risk ratio of 0·95 (95% CI 0·86–1·04; p=0· 233). Reasons for the differences in ELFIN trial results and other studies may include population differences, the routine use of antifungals in the UK, timing of administration of the lactoferrin in relation to disease onset, or specific properties of the lactoferrin used in different trials. Further exploration is being undertaken in the UK NIHR funded Mechanisms Affecting the Guts of Preterm Infants in Enteral feeding trials (MAGPIE) study, for which results should be available soon.

scholarly journals Protocol for the Lactoferrin Infant Feeding Trial (LIFT): a randomised trial of adding lactoferrin to the feeds of very-low birthweight babies prior to hospital discharge

BMJ Open ◽  
2018 ◽  
Vol 8 (10) ◽  
pp. e023044 ◽  
Author(s):  
Andrew Martin ◽  
Alpana Ghadge ◽  
Paolo Manzoni ◽  
Kei Lui ◽  
Rebecca Brown ◽  
...  
Keyword(s):  
Brain Injury ◽  
Hospital Discharge ◽  
Low Birthweight ◽  
Late Onset ◽  
Randomised Trial ◽  
Control Group ◽  
Bovine Lactoferrin ◽  
Very Low Birthweight ◽  
End Point ◽  
Late Onset Sepsis

IntroductionVery-low birthweight (VLBW, <1500 g) infants comprise about 1%–1.4% of all births in high-income countries. Every year, about 3000 VLBW babies in Australia and New Zealand receive intensive care. Many die or else survive with severe brain injury, retinopathy, late-onset sepsis or necrotising enterocolitis (NEC), each of which carries substantial risk of disability.Methods and analysisThis trial tests whether adding bovine lactoferrin (bLF) to feeds in VLBW infants improves (1) survival to hospital discharge free from brain injury, late-onset sepsis, NEC and treated retinopathy of prematurity (primary composite end point); (2) each component of the primary composite end point and (3) time to reach full enteral feeds, number of blood transfusions, chronic lung disease and length of hospital stay. It includes a cost-effectiveness analysis of bLF in improving survival free from major morbidity, and evaluates the effect of bLF on survival and developmental outcomes at 24 to 36 months corrected gestational age.This is a multicentre, two-arm, randomised trial comparing the treatment group receiving bLF added to breast milk or formula milk daily (up to 250 mg/kg/day bLF) versus the control group receiving no bLF supplementation. The intervention is administered until 34 completed weeks corrected gestation or for 2 weeks, whichever is longer, or until discharge home, if earlier. The target sample size of 1500 participants yields 85% power, at the two-sided 5% level significance, to detect a difference in proportions meeting the primary outcome assuming the true probability is 74% in controls and 80.5% in the bLF group.Ethics and disseminationThis protocol was approved by Northern Sydney Local Human Research Ethics Committee in January 2017 (Version 2.0, Reference 1003-118M) and other relevant ethics committees. The findings of the trial will be disseminated through peer-reviewed journals and conference presentations.Trial registration numberACTRN12611000247976; Pre-results.

Effect of bovine lactoferrin on prevention of late-onset sepsis in infants <1500g: a pooled analysis of individual patient data from two randomized controlled trials.

2020 ◽  
Author(s):  
Theresa J. Ochoa ◽  
Sebastian Loli ◽  
Karina Mendoza ◽  
Cesar Carcamo ◽  
Sicilia Bellomo ◽  
...  
Keyword(s):  
Birth Weight ◽  
Human Milk ◽  
Randomized Controlled Trials ◽  
Late Onset ◽  
Milk Intake ◽  
Control Group ◽  
Controlled Trials ◽  
Bovine Lactoferrin ◽  
Randomized Controlled ◽  
Late Onset Sepsis

We previously conducted two randomized controlled trials of bovine lactoferrin (bLF) for prevention of late-onset sepsis (LOS) in infants with a birth weight <2500g (Study 1) and <2000g (Study 2). The aim of this study was to determine the effect of bLF on prevention of culture-proven or probable LOS in infants with a birth weight <1500g from both studies, and to determine the bLF effect depending on human milk intake. Both trial designs had similar inclusion and exclusion criteria, same bLF dose (200mg/kg/day) and same control (maltodextrin). We fitted multivariate Cox regression models to estimate the effect of bLF on the risk of development of the composite outcome, adjusting for covariates. We included 335 neonates with a mean birth weight of 1162g ±244g; 27.5% were <1000g. There were 33 first episodes of LOS in the bLF group and 48 in the control group (19.5% vs 28.9%). bLF had a protective effect on the risk of development LOS, Hazard Ratio (HR) 0.64 (%95CI: 0.41-0.99,p=0.048); particularly among infants <1000g, HR 0.46 (%95CI: 0.22-0.96,p=0.039) and among infants with low human milk intake, HR 0.40 (%95CI: 0.19-0.84,p=0.015). bLF supplementation protects against LOS in infants <1500g, especially among infants not receiving human milk.

scholarly journals Oropharyngeal Administration of Colostrum for Preventing Necrotizing Enterocolitis and Late-onset Sepsis in Preterm Infants with Gestational Age ≤ 32 Weeks: A Single-center Randomized Controlled Trial

2021 ◽  
Author(s):  
xia ouyang ◽  
changyi yang ◽  
wenlong xiu ◽  
yanhua hu ◽  
susu mei ◽  
...  
Keyword(s):  
Preterm Infants ◽  
Necrotizing Enterocolitis ◽  
Enteral Feeding ◽  
Gestational Age ◽  
Late Onset ◽  
Controlled Trial ◽  
Control Group ◽  
Clinical Trial Registry ◽  
Late Onset Sepsis ◽  
Full Enteral Feeding

Abstract BackgroundOropharyngeal administration of colostrum (OAC) may provide immunoprotective and anti-inflammatory effects that potentially reduce the incidence of necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) and improve short-term outcomes.ObjectiveTo evaluate the role of OAC in the early prevention of NEC and LOS in preterm infants with gestational age (GA) ≤ 32 weeks.MethodsA randomized, placebo-controlled trial was conducted in a 40-bed tertiary neonatal intensive care unit (NICU) in China. Preterm infants with GA ≤ 32 weeks were divided randomly into an OAC group, which received 0.4 ml maternal colostrum smearing via the oropharyngeal route every 3 hours for 10 days beginning within the first 48 hours after birth, and a control group, which received normal saline instead. Data from the two groups were collected and compared.ResultsA total of 127 patients in the OAC group and 125 patients in the control group were finally enrolled. The incidence of NEC (Bell stage 2 or 3) and LOS was lower in the OAC group [2.4% vs. 10.4%, χ2 = 6.845, ༰=0.009; 4.7% vs. 13.6%, χ2 = 5.983, ༰=0.014]. In addition, the incidence of intraventricular hemorrhage (IVH) (stage 3 or 4) was lower [1.6% vs. 7.2%,χ2 = 4.775, ༰=0.029], and the time of achieving full enteral feeding was shorter [ 22.0 days vs. 25.0 days༌Z = 6༌424.500༌P = 0.009)] in the OAC group. No cases of adverse reactions were observed in either group.ConclusionsOAC is a safe and simple NICU procedure that yields a potential advantage in decreasing the incidence of NEC, LOS, and severe IVH and shortening the time to achieve full enteral feeding in preterm infants with GA ≤ 32 weeks.Trial registrationChinese Clinical Trial Registry, ChiCTR1900023697, Registered 8 June 2019, Retrospectively registered, http://www.chictr.org.cn/edit.aspx? pid = 39398

Zinc Supplementation in Preterm Neonates with Late-Onset Sepsis: Is It Beneficial?

2020 ◽  
Author(s):  
Mohamed Shawky Elfarargy ◽  
Ghada Al-Ashmawy ◽  
Sally Abu-Risha ◽  
Haidy Khattab
Keyword(s):  
Late Onset ◽  
Intervention Group ◽  
Preterm Neonates ◽  
Control Group ◽  
P Value ◽  
Late Onset Sepsis ◽  
Sepsis Score ◽  
The Mean ◽  
And Control ◽  
Group 1

Objective Neonatal sepsis (NS) is a serious neonatal disease. The aim of this study was to detect the role of zinc (Zn) supplementation in preterm neonates with late-onset sepsis (LOS). Study Design A prospective randomized clinical trial study which was done at Tanta University Hospital from August 2016 to March 2018 on 180 preterm neonates with LOS. The studied neonates were divided into two groups: group 1 (90 neonates), which received Zn and antibiotics, and group 2 (90 neonates), which received antibiotics and placebo. In group 1, the neonates received 1.4 mg elemental Zn/kg/d orally for 10 days. Sepsis score, C-reactive protein (CRP), and procalcitonin (PCT) were done for both groups. Results As regards sepsis score, it showed that before beginning the treatment, there were 85 and 84 neonates who had high probable sepsis (HPS) in intervention and control groups, respectively, and this revealed nonstatistically significant difference (non-SSD) between both groups (p-value is 0.756) and after 10 days of treatment, there were 1 and 4 neonates who had HPS in intervention and control group, respectively, and this revealed SSD between both groups (p-value is 0.045*). As regards CRP and PCT, the results showed that before beginning the treatment, the mean ± standard deviation (SD) of CRP and PCT were 39.4 ± 10.1 mg/L and 5.2 + 1.8 ng/mL, respectively, in intervention group, while it was 39.6 + 9.9 mg/L and 5.1 + 1.9 ng/mL, respectively, in control group and this revealed non-SSD between both groups (p-value is 0.893 and 0.717, respectively) and after 10 days of treatment, the mean ± SD of CRP and PCT were 5.3 ± 1.8 mg/L and 0.39 ± 0.13 ng/mL, respectively, in intervention group and 6.1 + 2 mg/L and 0.61 + 0.22 ng/mL, respectively, in control group and this revealed SSD between both groups (p-value is 0.008* and 0.044*, respectively). Conclusion Zn supplementation in preterm neonates with LOS is beneficial in improving the clinical and laboratory finding. Recommendation Zn supplementation for preterm neonates with LOS. Key Points

scholarly journals Lactoferrin impact on gut microbiota in preterm infants with late-onset sepsis or necrotising enterocolitis: the MAGPIE mechanisms of action study

2021 ◽  
Vol 8 (14) ◽  
pp. 1-88
Author(s):  
Nicholas Embleton ◽  
Janet Berrington ◽  
Stephen Cummings ◽  
Jon Dorling ◽  
Andrew Ewer ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Preterm Infants ◽  
Late Onset ◽  
Disease Onset ◽  
Necrotising Enterocolitis ◽  
Liquid Chromatography Mass Spectrometry ◽  
Chromatography Mass Spectrometry ◽  
Late Onset Sepsis ◽  
The Impact

Background Preterm infants have high rates of morbidity, especially from late-onset sepsis and necrotising enterocolitis. Lactoferrin is an anti-infective milk protein that may act through effects on gut bacteria, metabolites and epithelial cell function. The impact of supplemental lactoferrin in reducing late-onset sepsis was explored in the Enteral LactoFerrin In Neonates (ELFIN) trial. Objectives The Mechanisms Affecting the Gut of Preterm Infants in Enteral feeding (MAGPIE) study was nested within the ELFIN trial and aimed to determine the impact of lactoferrin on gut microbiota and bacterial function, and changes preceding disease onset. We aimed to explore impacts on the stool bacteria and faecal/urinary metabolome using gas and liquid chromatography–mass spectrometry, and explore immunohistological pathways in resected tissue. Methods Preterm infants from 12 NHS hospitals were enrolled in the study, and daily stool and urine samples were collected. Local sample collection data were combined with ELFIN trial data from the National Perinatal Epidemiology Unit, Oxford. The longitudinal impact of lactoferrin in healthy infants was determined, and samples that were collected before disease onset were matched with samples from healthy control infants. Established, quality-controlled 16S ribonucleic acid, gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry analyses were conducted. Validated databases and standardised workflows were used to identify bacteria and metabolites. Tissue samples from infants undergoing surgery and matched controls were analysed. Results We recruited 479 preterm infants (mean gestation of 28.4 ± 2.3 weeks) and collected > 33,000 usable samples from 467 infants. 16S ribonucleic acid bacterial analysis was conducted on samples from 201 infants, of whom 20 had necrotising enterocolitis and 51 had late-onset sepsis, along with samples from healthy matched controls to explore longitudinal changes. The greatest change in relative bacterial abundance over time was observed in Staphylococcus, which decreased from 42% at aged 7–9 days to only 2% at aged 30–60 days (p < 0.001). Small but significant differences in community composition were observed between samples in each ELFIN trial group (R 2 = 0.005; p = 0.04). Staphylococcus (p < 0.01), Haemophilus (p < 0.01) and Lactobacillus (p = 0.01) showed greater mean relative abundance in the placebo group than in the lactoferrin group. Gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry analyses showed that lactoferrin had limited impact on the metabolome. Liquid chromatography–mass spectrometry showed significant metabolite differences between necrotising enterocolitis or late-onset sepsis infants and healthy controls. The resected gut tissue analysis revealed 82 differentially expressed genes between healthy and necrotic tissue. Limitations Although we recruited a large number of infants, collecting daily samples from every infant is challenging, especially in the few days immediately preceding disease onset. Conclusion We conducted a large mechanistic study across multiple hospital sites and showed that, although lactoferrin significantly decreased the level of Staphylococcus and other key pathogens, the impact was smaller than those of other clinical variables. Immunohistochemistry identified multiple inflammatory pathways leading to necrotising enterocolitis and showed that the use of NHS pathology archive tissue is feasible in the context of a randomised controlled trial. Future work We observed significant changes in the stool and urinary metabolome in cases preceding late-onset sepsis or necrotising enterocolitis, which provide metabolic targets for a future mechanistic and biomarker study. Trial registration Current Controlled Trials ISRCTN12554594. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 14. See the NIHR Journals Library website for further project information.

scholarly journals Comparison of the Phenotype and Outcome of Granulomatosis with Polyangiitis Between UK and Japanese Cohorts

2016 ◽  
Vol 44 (2) ◽  
pp. 216-222 ◽  
Author(s):  
Shunsuke Furuta ◽  
Afzal N. Chaudhry ◽  
Yoshihiro Arimura ◽  
Hiroaki Dobashi ◽  
Shouichi Fujimoto ◽  
...  
Keyword(s):  
United Kingdom ◽  
Granulomatosis With Polyangiitis ◽  
Age At Onset ◽  
Survival Rates ◽  
Disease Onset ◽  
Japanese Patients ◽  
Antineutrophil Cytoplasmic Antibodies ◽  
Respiratory Involvement ◽  
The United Kingdom ◽  
The Uk

Objective.There are differences in the frequencies of antineutrophil cytoplasmic antibodies (ANCA)–associated vasculitis subgroups between different geographic regions, and we have reported differences in the phenotype of microscopic polyangiitis between Europe and Japan. In this retrospective observational study, we compared phenotypes and outcomes of granulomatosis with polyangiitis (GPA) between the United Kingdom and Japan.Methods.We identified 128 UK and 82 Japanese patients with GPA diagnosed between 2000 and 2012. We evaluated baseline characteristics including ANCA status and organ involvement, treatment, patient and renal survival, and time to first relapse.Results.Median age at onset was higher in Japan than in the UK (62.2 yrs vs 57.5 yrs, p < 0.01). The proportion of patients with proteinase 3 (PR3)-ANCA was lower in Japan than in the UK (61.0% vs 85.2%, p < 0.01), while the proportion of myeloperoxidase-ANCA was higher in Japan than the UK (34.1% vs 8.6%, p < 0.01). Serum creatinine at diagnosis was lower in Japan than the UK (68.1 μmol/l vs 101.0 μmol/l, p < 0.01). Respiratory involvement was more frequent in Japan than the UK (69.5% vs 40.6%, p < 0.01). In both countries, most patients received both glucocorticoids and cyclophosphamide. At 60 months the cumulative survival rates were 87.6% and 94.3% in Japan and the UK, respectively (p = 0.03). At 60 months the cumulative relapse rates were 37.1% and 68.1% in Japan and the UK, respectively (p < 0.01).Conclusion.Japanese patients with GPA were older at disease onset, with less PR3-ANCA positivity, milder renal dysfunction, and more frequent respiratory involvement than UK patients. The relapse-free survival rate was higher in Japan than the United Kingdom.

scholarly journals Patterned progression of gut microbiota associated with necrotizing enterocolitis and late onset sepsis in preterm infants: a prospective study in a Chinese neonatal intensive care unit

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7310 ◽  
Author(s):  
Jiayi Liu ◽  
Yuqing Li ◽  
Yi Feng ◽  
Liya Pan ◽  
Zhoulonglong Xie ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Preterm Infants ◽  
Necrotizing Enterocolitis ◽  
Neonatal Intensive Care ◽  
Late Onset ◽  
Control Group ◽  
High Morbidity ◽  
Asian Populations ◽  
Late Onset Sepsis ◽  
Underlying Mechanisms

Necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) are two common premature birth complications with high morbidity and mortality. Recent studies in Europe and America have linked gut microbiota dysbiosis to their etiology. However, similar studies in Asian populations remain scant. In this pilot study, we profiled gut microbiota of 24 Chinese preterm infants from birth till death or discharge from NICU. Four of them developed NEC and three developed LOS. Unexpectedly, we detected highly-diversified microbiota with similar compositions in all patients shortly after birth. However, as patients aged, the microbial diversities in case groups differed significantly from that of the control group. These differences emerged after the third day of life and persisted throughout the course of both NEC and LOS. Using a Zero-Inflated Beta Regression Model with Random Effects (ZIBR), we detected higher Bacillus (p = 0.032) and Solibacillus (p = 0.047) before the onset of NEC and LOS. During NEC progression, Enterococcus, Streptococcus and Peptoclostridium were the dominant genera while during LOS progression; Klebsiella was the only dominant genus that was also detected by the diagnostic hemoculture. These results warrant further studies to identify causative microbial patterns and underlying mechanisms.

scholarly journals Oropharyngeal administration of colostrum for preventing necrotizing enterocolitis and late-onset sepsis in preterm infants with gestational age ≤ 32 weeks: a pilot single-center randomized controlled trial

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Xia OuYang ◽  
Chang-Yi Yang ◽  
Wen-Long Xiu ◽  
Yan-Hua Hu ◽  
Su-Su Mei ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Preterm Infants ◽  
Enteral Feeding ◽  
Late Onset ◽  
Controlled Trial ◽  
Control Group ◽  
Single Center ◽  
Randomized Controlled ◽  
Late Onset Sepsis ◽  
Full Enteral Feeding

Abstract Background Oropharyngeal administration of colostrum (OAC) may provide immunoprotective and anti-inflammatory effects that potentially reduce the incidence of necrotizing enterocolitis (NEC) and late-onset sepsis and improve short-term outcomes. Our objective was to evaluate the role of OAC in the early prevention of NEC and late-onset sepsis in preterm infants with gestational age (GA) ≤ 32 weeks. Methods A pilot, single-center, 1:1 parallel randomized controlled trial was conducted in a 40-bed tertiary neonatal intensive care unit (NICU) in China from 1 January 2019 to 30 September 2020. Preterm infants were randomly divided into two groups with GA ≤ 32 weeks. The OAC group included preterm infants who received 0.4 ml of maternal colostrum via the oropharyngeal route every 3 h for 10 days beginning within the first 48 h after birth, and the control group included preterm infants who received normal saline instead. Data from the two groups were collected and compared. Results A total of 127 infants in the OAC group and 125 infants in the control group were enrolled. The incidence of NEC (Bell stage 2 or 3) and late-onset sepsis were lower in the OAC group [2.36% vs. 10.40%, relative risk (RR) 0.23 (95% confidence interval (CI) 0.07, 0.78), adjusted RR 0.23 (95% CI 0.06, 0.84); 4.72% vs. 13.60%, RR 0.35 (95% CI 0.14, 0.85), adjusted RR 0.36 (95% CI 0.14, 0.95)]. In addition, the incidence of proven sepsis and intraventricular hemorrhage (IVH) (stage 3 or 4) were lower in the OAC group [2.36% vs. 8.80%, RR 0.27 (95% CI 0.08, 0.94); 1.57% vs. 7.20%, RR 0.22 (95% CI 0.05, 0.99)], and the time to achieve full enteral feeding was shorter (23.13 ± 9.45 days vs. 28.50 ± 14.80 days). No adverse reactions were observed in either group. Conclusions Oropharyngeal administration of colostrum is a safe and simple NICU procedure that may yield a potential effect in decreasing the incidences of NEC, late-onset sepsis, and severe IVH and shorten the time to achieve full enteral feeding in preterm infants with GA ≤ 32 weeks. Trial registration Chinese Clinical Trial Registry, ChiCTR1900023697, Registered 8 June 2019, retrospectively registered.

TBE in United Kingdom

2020 ◽  
Keyword(s):  
United Kingdom ◽  
Clinical Disease ◽  
England And Wales ◽  
Probable Case ◽  
The United Kingdom ◽  
South West ◽  
Louping Ill ◽  
The Uk ◽  
North And South ◽  
South West England

Until 2019, TBE was considered only to be an imported disease to the United Kingdom. In that year, evidence became available that the TBEV is likely circulating in the country1,2 and a first “probable case” of TBE originating in the UK was reported.3 In addition to TBEV, louping ill virus (LIV), a member of the TBEV-serocomplex, is also endemic in parts of the UK. Reports of clinical disease caused by LIV in livestock are mainly from Scotland, parts of North and South West England and Wales.4

Risk Transferin Public Private Partnership/Private Finance Initiative Procurement Documents:The Differencebetween The United Kingdom and Malaysia

2016 ◽  
Vol 4 (4) ◽  
pp. 30
Author(s):  
Nooriha Abdullah ◽  
Darinka Asenova ◽  
Stephen J. Bailey
Keyword(s):  
United Kingdom ◽  
Public Procurement ◽  
Research Question ◽  
Public Private Partnership ◽  
Private Finance Initiative ◽  
Private Partnership ◽  
Risk Transfer ◽  
Private Finance ◽  
The United Kingdom ◽  
The Uk

The aim of this paper is to analyse the risk transfer issue in Public Private Partnership/Private Finance Initiative (PPP/PFI) procurement documents in the United Kingdom (UK) and Malaysia. It utilises qualitative research methods using documentation and interviews for data collection. The UK documents (guidelines and contracts) identify the risks related to this form of public procurement of services and makeexplicittheappropriateallocation of those risks between the public and the private sector PPP/PFI partners and so the types of risks each party should bear. However, in Malaysia, such allocation of risks was not mentioned in PPP/PFI guidelines. Hence, a question arises regarding whether risk transfer exists in Malaysian PPP/PFI projects, whether in contracts or by other means. This research question is the rationale for the comparative analysis ofdocumentsand practicesrelatingtorisk transfer in the PPP/PFI procurements in both countries. The results clarify risk-related issues that arise in implementing PPP/PFI procurement in Malaysia, in particular how risk is conceptualised, recognised and allocated (whether explicitly or implicitly), whether or not that allocation is intended to achieve optimum risk transfer, and so the implications forachievement ofvalue for moneyor other such objectivesinPPP/PFI.

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