Publications by authors named "Nicholas Longford"

27 Publications

  • Page 1 of 1

Early versus later initiation of parenteral nutrition for very preterm infants: a propensity score-matched observational study.

Arch Dis Child Fetal Neonatal Ed 2021 Nov 18. Epub 2021 Nov 18.

Department of Neonatal Medicine, Imperial College London, London, UK.

Objective: To evaluate the impact of timing of initiation of parenteral nutrition (PN) after birth in very preterm infants.

Design: Propensity-matched analysis of data from the UK National Neonatal Research Database.

Patients: 65 033 babies <31 weeks gestation admitted to neonatal units in England and Wales between 2008 and 2019.

Interventions: PN initiated in the first 2 days (early) versus after the second postnatal day (late). Babies who died in the first 2 days without receiving PN were analysed as 'late'.

Main Outcome Measures: The main outcome measure was morbidity-free survival to discharge. The secondary outcomes were survival to discharge, growth and other core neonatal outcomes.

Findings: No difference was found in the primary outcome (absolute rate difference (ARD) between early and late 0.50%, 95% CI -0.45 to 1.45, p=0.29). The early group had higher rates of survival to discharge (ARD 3.3%, 95% CI 2.7 to 3.8, p<0.001), late-onset sepsis (ARD 0.84%, 95% CI 0.48 to 1.2, p<0.001), bronchopulmonary dysplasia (ARD 1.24%, 95% CI 0.30 to 2.17, p=0.01), treated retinopathy of prematurity (ARD 0.50%, 95% CI 0.17 to 0.84, p<0.001), surgical procedures (ARD 0.80%, 95% CI 0.20 to 1.40, p=0.01) and greater drop in weight z-score between birth and discharge (absolute difference 0.019, 95% CI 0.003 to 0.035, p=0.02). Of 4.9% of babies who died in the first 2 days, 3.4% were in the late group and not exposed to PN.

Conclusions: Residual confounding and survival bias cannot be excluded and justify the need for a randomised controlled trial powered to detect differences in important functional outcomes.
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http://dx.doi.org/10.1136/archdischild-2021-322383DOI Listing
November 2021

Changes in neonatal admissions, care processes and outcomes in England and Wales during the COVID-19 pandemic: a whole population cohort study.

BMJ Open 2021 10 1;11(10):e054410. Epub 2021 Oct 1.

Section of Neonatal Medicine, School of Public Health, Faculty of Medicine, Imperial College London, London, UK

Objectives: The COVID-19 pandemic instigated multiple societal and healthcare interventions with potential to affect perinatal practice. We evaluated population-level changes in preterm and full-term admissions to neonatal units, care processes and outcomes.

Design: Observational cohort study using the UK National Neonatal Research Database.

Setting: England and Wales.

Participants: Admissions to National Health Service neonatal units from 2012 to 2020.

Main Outcome Measures: Admissions by gestational age, ethnicity and Index of Multiple Deprivation, and key care processes and outcomes.

Methods: We calculated differences in numbers and rates between April and June 2020 (spring), the first 3 months of national lockdown (COVID-19 period), and December 2019-February 2020 (winter), prior to introduction of mitigation measures, and compared them with the corresponding differences in the previous 7 years. We considered the COVID-19 period highly unusual if the spring-winter difference was smaller or larger than all previous corresponding differences, and calculated the level of confidence in this conclusion.

Results: Marked fluctuations occurred in all measures over the 8 years with several highly unusual changes during the COVID-19 period. Total admissions fell, having risen over all previous years (COVID-19 difference: -1492; previous 7-year difference range: +100, +1617; p<0.001); full-term black admissions rose (+66; -64, +35; p<0.001) whereas Asian (-137; -14, +101; p<0.001) and white (-319; -235, +643: p<0.001) admissions fell. Transfers to higher and lower designation neonatal units increased (+129; -4, +88; p<0.001) and decreased (-47; -25, +12; p<0.001), respectively. Total preterm admissions decreased (-350; -26, +479; p<0.001). The fall in extremely preterm admissions was most marked in the two lowest socioeconomic quintiles.

Conclusions: Our findings indicate substantial changes occurred in care pathways and clinical thresholds, with disproportionate effects on black ethnic groups, during the immediate COVID-19 period, and raise the intriguing possibility that non-healthcare interventions may reduce extremely preterm births.
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http://dx.doi.org/10.1136/bmjopen-2021-054410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488283PMC
October 2021

Outcomes in relation to early parenteral nutrition use in preterm neonates born between 30 and 33 weeks' gestation: a propensity score matched observational study.

Arch Dis Child Fetal Neonatal Ed 2021 Sep 21. Epub 2021 Sep 21.

Neonatal Medicine, Imperial College London, London, UK.

Objective: To evaluate whether in preterm neonates parenteral nutrition use in the first 7 postnatal days, compared with no parenteral nutrition use, is associated with differences in survival and other important morbidities. Randomised trials in critically ill older children show that harms, such as nosocomial infection, outweigh benefits of early parenteral nutrition administration; there is a paucity of similar data in neonates.

Design: Retrospective cohort study using propensity matching including 35 maternal, infant and organisational factors to minimise bias and confounding.

Setting: National, population-level clinical data obtained for all National Health Service neonatal units in England and Wales.

Patients: Preterm neonates born between 30 and 32 weeks.

Interventions: The exposure was parenteral nutrition administered in the first 7 days of postnatal life; the comparator was no parenteral nutrition.

Main Outcome Measures: The primary outcome was survival to discharge from neonatal care. Secondary outcomes comprised the neonatal core outcome set.

Results: 16 292 neonates were compared in propensity score matched analyses. Compared with matched neonates not given parenteral nutrition in the first postnatal week, neonates who received parenteral nutrition had higher survival at discharge (absolute rate increase 0.91%; 95% CI 0.53% to 1.30%), but higher rates of necrotising enterocolitis (absolute rate increase 4.6%), bronchopulmonary dysplasia (absolute rate increase 3.9%), late-onset sepsis (absolute rate increase 1.5%) and need for surgical procedures (absolute rate increase 0.92%).

Conclusions: In neonates born between 30 and 32 weeks' gestation, those given parenteral nutrition in the first postnatal week had a higher rate of survival but higher rates of important neonatal morbidities. Clinician equipoise in this area should be resolved by prospective randomised trials.

Trial Registration Number: NCT03767634.
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http://dx.doi.org/10.1136/archdischild-2021-321643DOI Listing
September 2021

Nutritional management in newborn babies receiving therapeutic hypothermia: two retrospective observational studies using propensity score matching.

Health Technol Assess 2021 06;25(36):1-106

Neonatal Medicine, School of Public Health, Faculty of Medicine, Imperial College London, London, UK.

Background: Therapeutic hypothermia is standard of care for babies with moderate to severe hypoxic-ischaemic encephalopathy. There is limited evidence to inform provision of nutrition during hypothermia.

Objectives: To assess the association during therapeutic hypothermia between (1) enteral feeding and outcomes, such as necrotising enterocolitis and (2) parenteral nutrition and outcomes, such as late-onset bloodstream infection.

Design: A retrospective cohort study using data held in the National Neonatal Research Database and applying propensity score methodology to form matched groups for analysis.

Setting: NHS neonatal units in England, Wales and Scotland.

Participants: Babies born at ≥ 36 gestational weeks between 1 January 2010 and 31 December 2017 who received therapeutic hypothermia for 72 hours or who died during treatment.

Interventions: Enteral feeding analysis - babies who were enterally fed during therapeutic hypothermia (intervention) compared with babies who received no enteral feeds during therapeutic hypothermia (control). Parenteral nutrition analysis - babies who received parenteral nutrition during therapeutic hypothermia (intervention) compared with babies who received no parenteral nutrition during therapeutic hypothermia (control).

Outcome Measures: Primary outcomes were severe and pragmatically defined necrotising enterocolitis (enteral feeding analysis) and late-onset bloodstream infection (parenteral nutrition analysis). Secondary outcomes were survival at neonatal discharge, length of neonatal stay, breastfeeding at discharge, onset of breastfeeding, time to first maternal breast milk, hypoglycaemia, number of days with a central line in situ, duration of parenteral nutrition, time to full enteral feeds and growth.

Results: A total of 6030 babies received therapeutic hypothermia. Thirty-one per cent of babies received enteral feeds and 25% received parenteral nutrition. Seven babies (0.1%) were diagnosed with severe necrotising enterocolitis, and further comparative analyses were not conducted on this outcome. A total of 3236 babies were included in the matched enteral feeding analysis. Pragmatically defined necrotising enterocolitis was rare in both groups (0.5% vs. 1.1%) and was lower in babies who were fed during hypothermia (rate difference -0.5%, 95% confidence interval -1.0% to -0.1%;  = 0.03). Higher survival to discharge (96.0% vs. 90.8%, rate difference 5.2%, 95% confidence interval 3.9% to 6.6%;  < 0.001) and higher breastfeeding at discharge (54.6% vs. 46.7%, rate difference 8.0%, 95% confidence interval 5.1% to 10.8%;  < 0.001) rates were observed in enterally fed babies who also had a shorter neonatal stay (mean difference -2.2 days, 95% confidence interval -3.0 to -1.2 days). A total of 2480 babies were included in the matched parenteral nutrition analysis. Higher levels of late-onset bloodstream infection were seen in babies who received parenteral nutrition (0.3% vs. 0.9%, rate difference 0.6%, 95% confidence interval 0.1% to 1.2%;  = 0.03). Survival was lower in babies who did not receive parenteral nutrition (90.0% vs. 93.1%, rate difference 3.1%, 95% confidence interval 1.5% to 4.7%;  < 0.001).

Limitations: Propensity score methodology can address imbalances in observed confounders only. Residual confounding by unmeasured or poorly recorded variables cannot be ruled out. We did not analyse by type or volume of enteral or parenteral nutrition.

Conclusions: Necrotising enterocolitis is rare in babies receiving therapeutic hypothermia, and the introduction of enteral feeding is associated with a lower risk of pragmatically defined necrotising enterocolitis and other beneficial outcomes, including rates of higher survival and breastfeeding at discharge. Receipt of parenteral nutrition during therapeutic hypothermia is associated with a higher rate of late-onset infection but lower mortality. These results support introduction of enteral feeding during therapeutic hypothermia.

Future Work: Randomised trials to assess parenteral nutrition during therapeutic hypothermia.

Trial Registration: Current Controlled Trials ISRCTN474042962.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 36. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215569PMC
June 2021

Administration of parenteral nutrition during therapeutic hypothermia: a population level observational study using routinely collected data held in the National Neonatal Research Database.

Arch Dis Child Fetal Neonatal Ed 2021 Nov 5;106(6):608-613. Epub 2021 May 5.

Division of Neonatal-Perinatal Medicine, Dalhousie University-Faculty of Medicine, Halifax, Nova Scotia, Canada.

Background: Parenteral nutrition is commonly administered during therapeutic hypothermia. Randomised trials in critically ill children indicate that parenteral nutrition may be harmful.

Objective: To examine the association between parenteral nutrition during therapeutic hypothermia and clinically important outcomes.

Design: Retrospective, population-based cohort study using the National Neonatal Research Database; propensity scores were used to create matched groups for comparison.

Setting: National Health Service neonatal units in England, Scotland and Wales.

Participants: 6030 term and near-term babies, born 1/1/2010 and 31/12/2017, who received therapeutic hypothermia; 2480 babies in the matched analysis.

Exposure: We compared babies that received any parenteral nutrition during therapeutic hypothermia with babies that did not.

Main Outcome Measures: Primary outcome: blood culture confirmed late-onset infection; secondary outcomes: treatment for late onset infection, necrotising enterocolitis, survival, length of stay, measures of breast feeding, hypoglycaemia, central line days, time to full enteral feeds, discharge weight.

Results: 1475/6030 babies (25%) received parenteral nutrition. In comparative matched analyses, the rate of culture positive late onset infection was higher in babies that received parenteral nutrition (0.3% vs 0.9%; difference 0.6; 95% CI 0.1, 1.2; p=0.03), but treatment for presumed infection was not (difference 0.8%, 95% CI -2.1 to 3.6, p=0.61). Survival was higher in babies that received parenteral nutrition (93.1% vs 90.0%; rate difference 3.1, 95% CI 1.5, 4.7; p<0.001).

Conclusions: Receipt of parenteral nutrition during therapeutic hypothermia is associated with higher late-onset infection but lower mortality. This finding may be explained by residual confounding. Research should address the risks and benefits of parenteral nutrition in this population.
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http://dx.doi.org/10.1136/archdischild-2020-321299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8543212PMC
November 2021

Feeding during neonatal therapeutic hypothermia, assessed using routinely collected National Neonatal Research Database data: a retrospective, UK population-based cohort study.

Lancet Child Adolesc Health 2021 06 21;5(6):408-416. Epub 2021 Apr 21.

Division of Neonatal-Perinatal Medicine, Faculty of Medicine, Dalhousie University, IWK Health Centre, Halifax, NS, Canada.

Background: Therapeutic hypothermia is standard of care in high-income countries for babies born with signs of hypoxic ischaemic encephalopathy, but optimal feeding during treatment is uncertain and practice is variable. This study aimed to assess the association between feeding during therapeutic hypothermia and clinically important outcomes.

Methods: We did a population-level retrospective cohort study using the UK National Neonatal Research Database. We included all babies admitted to National Health Service neonatal units in England, Scotland, and Wales between Jan 1, 2010, and Dec 31, 2017, who received therapeutic hypothermia for 72 h or died during this period. For analysis, we created matched groups using propensity scores and compared outcomes in babies who were fed versus unfed enterally during therapeutic hypothermia. The primary outcome was severe necrotising enterocolitis, either confirmed at surgery or causing death. Secondary outcomes include pragmatically defined necrotising enterocolitis (a recorded diagnosis of necrotising enterocolitis in babies who received at least 5 consecutive days of antibiotics while also nil by mouth during their neonatal unit stay), late-onset infection (pragmatically defined as 5 consecutive days of antibiotic treatment commencing after day 3), survival to discharge, measures of breastmilk feeding, and length of stay in neonatal unit.

Findings: 6030 babies received therapeutic hypothermia, of whom 1873 (31·1%) were fed during treatment. Seven (0·1%) babies were diagnosed with severe necrotising enterocolitis and the number was too small for further analyses. We selected 3236 (53·7%) babies for the matched feeding analysis (1618 pairs), achieving a good balance for all recorded background variables. Pragmatically defined necrotising enterocolitis was rare in both groups (incidence 0·5%, 95% CI 0·2-0·9] in the fed group vs 1·1% [0·7-1·4] in the unfed group). The enterally fed group had fewer pragmatically defined late-onset infections (difference -11·6% [95% CI -14·0 to -9·3]; p<0·0001), higher survival to discharge (5·2% [3·9-6·6]; p<0·0001), higher proportion of breastfeeding at discharge (8·0% [5·1-10·8]; p<0·0001), and shorter neonatal unit stays (-2·2 [-3·0 to -1·2] days; p<0·0001) compared with the unfed group.

Interpretation: Necrotising enterocolitis is rare in babies receiving therapeutic hypothermia. Enteral feeding during hypothermia is safe and associated with beneficial outcomes compared with not feeding, although residual confounding could not be completely ruled out. Our findings support starting milk feeds during therapeutic hypothermia.

Funding: UK National Institute for Health Research Health Technology Assessment programme 16/79/13.
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http://dx.doi.org/10.1016/S2352-4642(21)00026-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131202PMC
June 2021

Changing clinical characteristics of infants treated for hypoxic-ischaemic encephalopathy in England, Wales and Scotland: a population-based study using the National Neonatal Research Database.

Arch Dis Child Fetal Neonatal Ed 2021 Sep 4;106(5):501-508. Epub 2021 Feb 4.

Neonatal Medicine, School of Public Health, Faculty of Medicine, Imperial College London Faculty of Medicine, London, UK

Background: Therapeutic hypothermia is standard of care for babies with moderate/severe hypoxic-ischaemic encephalopathy and is increasingly used for mild encephalopathy.

Objective: Describe temporal trends in the clinical condition of babies diagnosed with hypoxic-ischaemic encephalopathy who received therapeutic hypothermia.

Design: Retrospective cohort study using data held in the National Neonatal Research Database.

Setting: National Health Service neonatal units in England, Wales and Scotland.

Patients: Infants born from 1 January 2010 to 31 December 2017 with a recorded diagnosis of hypoxic-ischaemic encephalopathy who received therapeutic hypothermia for at least 3 days or died in this period.

Main Outcomes: Primary outcomes: recorded clinical characteristics including umbilical cord pH; Apgar score; newborn resuscitation; seizures and treatment on day 1.

Secondary Outcomes: recorded hypoxic-ischaemic encephalopathy grade.

Results: 5201 babies with a diagnosis of hypoxic-ischaemic encephalopathy received therapeutic hypothermia or died; annual numbers increased over the study period. A decreasing proportion had clinical characteristics of severe hypoxia ischaemia or a diagnosis of moderate or severe hypoxic-ischaemic encephalopathy, trends were statistically significant and consistent across multiple clinical characteristics used as markers of severity.

Conclusions: Treatment with therapeutic hypothermia for hypoxic-ischaemic encephalopathy has increased in England, Scotland and Wales. An increasing proportion of treated infants have a diagnosis of mild hypoxic-ischaemic encephalopathy or have less severe clinical markers of hypoxia. This highlights the importance of determining the role of hypothermia in mild hypoxic-ischaemic encephalopathy. Receipt of therapeutic hypothermia is unlikely to be a useful marker for assessing changes in the incidence of brain injury over time.
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http://dx.doi.org/10.1136/archdischild-2020-319685DOI Listing
September 2021

Effect of surfactant dose on outcomes in preterm infants with respiratory distress syndrome: the OPTI-SURF study protocol.

BMJ Open 2020 12 12;10(12):e038959. Epub 2020 Dec 12.

Neonatal Medicine, School of Public Health, Faculty of Medicine, Imperial College London, London, UK.

Introduction: Respiratory distress syndrome is a condition seen in preterm infants primarily due to surfactant insufficiency. European guidelines recommend the dose and method of surfactant administration. However, in routine practice, clinicians often use a 'whole vial' approach to surfactant dosing. The aim of this study is to assess whether in preterm infants of gestational age 36 weeks or less, a low first dose of surfactant (100-130 mg/kg) compared with a high first dose (170-200 mg/kg) affects survival with no mechanical ventilation on either on postnatal days 3 and 4, and other outcomes.

Methods And Analysis: In this prospective, observational study, we will use the National Neonatal Research Database as the main data source. We will obtain additional information describing the dose and method of surfactant administration through the neonatal EPR system. We will use propensity scores to form matched groups with low first dose and high first dose for comparison.

Ethics And Dissemination: This study was approved by the West Midlands-Black Country Research Ethics Committee (REC reference: 18/WM/0132; IRAS project ID: 237111). The results of the research will be made publicly available through presentations at local, national or international conferences and will be submitted for publication in a peer-reviewed journal.

Trial Registration Number: NCT03808402; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2020-038959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735095PMC
December 2020

Association of early postnatal transfer and birth outside a tertiary hospital with mortality and severe brain injury in extremely preterm infants: observational cohort study with propensity score matching.

BMJ 2019 10 16;367:l5678. Epub 2019 Oct 16.

Section of Neonatal Medicine, Department of Medicine, Chelsea and Westminster campus, Imperial College London, London SW10 9NH, UK

Objective: To determine if postnatal transfer or birth in a non-tertiary hospital is associated with adverse outcomes.

Design: Observational cohort study with propensity score matching.

Setting: National health service neonatal care in England; population data held in the National Neonatal Research Database.

Participants: Extremely preterm infants born at less than 28 gestational weeks between 2008 and 2015 (n=17 577) grouped based on birth hospital and transfer within 48 hours of birth: upward transfer (non-tertiary to tertiary hospital, n=2158), non-tertiary care (born in non-tertiary hospital; not transferred, n=2668), and controls (born in tertiary hospital; not transferred, n=10 866). Infants were matched on propensity scores and predefined background variables to form subgroups with near identical distributions of confounders. Infants transferred between tertiary hospitals (horizontal transfer) were separately matched to controls in a 1:5 ratio.

Main Outcome Measures: Death, severe brain injury, and survival without severe brain injury.

Results: 2181 infants, 727 from each group (upward transfer, non-tertiary care, and control) were well matched. Compared with controls, infants in the upward transfer group had no significant difference in the odds of death before discharge (odds ratio 1.22, 95% confidence interval 0.92 to 1.61) but significantly higher odds of severe brain injury (2.32, 1.78 to 3.06; number needed to treat (NNT) 8) and significantly lower odds of survival without severe brain injury (0.60, 0.47 to 0.76; NNT 9). Compared with controls, infants in the non-tertiary care group had significantly higher odds of death (1.34, 1.02 to 1.77; NNT 20) but no significant difference in the odds of severe brain injury (0.95, 0.70 to 1.30) or survival without severe brain injury (0.82, 0.64 to 1.05). Compared with infants in the upward transfer group, infants in the non-tertiary care group had no significant difference in death before discharge (1.10, 0.84 to 1.44) but significantly lower odds of severe brain injury (0.41, 0.31 to 0.53; NNT 8) and significantly higher odds of survival without severe brain injury (1.37, 1.09 to 1.73; NNT 14). No significant differences were found in outcomes between the horizontal transfer group (n=305) and controls (n=1525).

Conclusions: In extremely preterm infants, birth in a non-tertiary hospital and transfer within 48 hours are associated with poor outcomes when compared with birth in a tertiary setting. We recommend perinatal services promote pathways that facilitate delivery of extremely preterm infants in tertiary hospitals in preference to postnatal transfer.
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http://dx.doi.org/10.1136/bmj.l5678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812621PMC
October 2019

Outcomes following early parenteral nutrition use in preterm neonates: protocol for an observational study.

BMJ Open 2019 07 9;9(7):e029065. Epub 2019 Jul 9.

Section of Neonatal Medicine, Imperial College London, London, UK.

Introduction: Preterm babies are among the highest users of parenteral nutrition (PN) of any patient group, but there is wide variation in commencement, duration, and composition of PN and uncertainty around which groups will benefit from early introduction. Recent studies in critically unwell adults and children suggest that harms, specifically increased rates of nosocomial infection, outweigh the benefits of early administration of PN. In this study, we will describe early PN use in neonatal units in England, Wales and Scotland. We will also evaluate if this is associated with differences in important neonatal outcomes in neonates born between 30 and 32 weeks gestation.

Methods And Analysis: We will use routinely collected data from all neonatal units in England, Wales and Scotland, available in the National Neonatal Research Database (NNRD). We will describe clinical practice in relation to any use of PN during the first 7 postnatal days among neonates admitted to neonatal care between 1 January 2012 and 31 December 2017. We will compare outcomes in neonates born between 30 and 32 weeks gestation who did or did not receive PN in the first week after birth using a propensity score-matched approach. The primary outcome will be survival to discharge home. Secondary outcomes will include components of the neonatal core outcome set: outcomes identified as important by former patients, parents, clinicians and researchers.

Ethics And Dissemination: We have obtained UK National Research Ethics Committee approval for this study (Ref: 18/NI/0214). The results of this study will be presented at academic conferences; the UK charity Bliss will aid dissemination to former patients and parents.

Trial Registration Number: NCT03767634.
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http://dx.doi.org/10.1136/bmjopen-2019-029065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615825PMC
July 2019

A Mixed Lipid Emulsion Containing Fish Oil and Its Effect on Electrophysiological Brain Maturation in Infants of Extremely Low Birth Weight: A Secondary Analysis of a Randomized Clinical Trial.

J Pediatr 2019 08 25;211:46-53.e2. Epub 2019 Apr 25.

Department of Pediatrics and Adolescent Medicine, Division of Neonatology, Pediatric Intensive Care Medicine and Neuropediatrics, Medical University of Vienna, Austria.

Objective: To assess whether parenteral nutrition for infants of extremely low birth weight using a mixed lipid emulsion that contains fish oil influences electrophysiological brain maturation.

Study Design: The study is a prespecified secondary outcome analysis of a randomized controlled trial of 230 infants of extremely low birth weight receiving a mixed (soybean oil, medium-chain triglycerides, olive oil, and fish oil; intervention) or a soybean oil-based lipid emulsion (control). The study was conducted at a single-level IV neonatal care unit (Medical University Vienna; June 2012 to October 2015). Electrophysiological brain maturation (background activity, sleep-wake cycling, and brain maturational scores) was assessed biweekly by amplitude-integrated electroencephalography (birth to discharge).

Results: A total of 317 amplitude-integrated electroencephalography measurements (intervention: n = 165; control: n = 152) from 121 (intervention: n = 63; control: n = 58) of 230 infants of the core study were available for analysis. Demographic characteristics were not significantly different. By 28 weeks of postmenstrual age, infants receiving the intervention displayed significantly greater percentages of continuous background activity. Total maturational scores and individual scores for continuity, cycling, and bandwidth were significantly greater. Maximum maturational scores were reached 2 weeks earlier in the intervention group (36.4 weeks, 35.4-37.5) compared with the control group (38.4 weeks, 37.1-42.4) (median, IQR; P < .001).

Conclusions: Using a mixed parenteral lipid emulsion that contains fish oil, we found that electrophysiological brain maturation was accelerated in infants who were preterm.

Trial Registration: ClinicalTrials.gov: NCT01585935.
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http://dx.doi.org/10.1016/j.jpeds.2019.03.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115932PMC
August 2019

Parent, patient and clinician perceptions of outcomes during and following neonatal care: a systematic review of qualitative research.

BMJ Paediatr Open 2018 9;2(1):e000343. Epub 2018 Oct 9.

Neonatal Medicine, Imperial College London, London, UK.

Objective: Multiple outcomes can be measured in infants that receive neonatal care. It is unknown whether outcomes of importance to parents and patients differ from those of health professionals. Our objective was to systematically map neonatal care outcomes discussed in qualitative research by patients, parents and healthcare professionals and test whether the frequency with which outcomes are discussed differs between groups.

Design: Systematic review of qualitative literature. The following databases were searched: Medline, CINAHL, EMBASE, PsycINFO and ASSIA from 1997 to 2017. Publications describing qualitative data relating to neonatal care outcomes, reported by former patients, parents or healthcare professionals, were included. Narrative text was analysed and outcomes grouped thematically by organ system. Permutation testing was applied to assess an association between the outcomes identified and stakeholder group.

Results: Sixty-two papers containing the views of over 4100 stakeholders were identified; 146 discrete outcomes were discussed; 58 outcomes related to organ systems and 88 to other more global domains. Permutation testing provides evidence that parents, former patients and health professionals reported outcomes with different frequencies (p=0.037).

Conclusions: Parents, patients and health professionals focus on different outcomes when discussing their experience of neonatal care. A wide range of neonatal care outcomes are reported in qualitative research; many are global outcomes relating to the overall status of the infant. The views of former patients and parents should be taken into consideration when designing research; the development of a core outcomes set for neonatal research will facilitate this.
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http://dx.doi.org/10.1136/bmjpo-2018-000343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203019PMC
October 2018

Optimising nutrition during therapeutic hypothermia.

Arch Dis Child Fetal Neonatal Ed 2019 May 15;104(3):F230-F231. Epub 2018 Oct 15.

Section of Neonatal Medicine, Department of Medicine, Imperial College London, London, UK.

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http://dx.doi.org/10.1136/archdischild-2018-315393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764248PMC
May 2019

Efficacy and safety of prostate artery embolization for benign prostatic hyperplasia: an observational study and propensity-matched comparison with transurethral resection of the prostate (the UK-ROPE study).

BJU Int 2018 08 6;122(2):270-282. Epub 2018 May 6.

Department of Interventional Radiology, Southampton General Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, UK.

Objectives: To assess the efficacy and safety of prostate artery embolization (PAE) for lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) and to conduct an indirect comparison of PAE with transurethral resection of the prostate (TURP).

Patients And Methods: As a joint initiative between the British Society of Interventional Radiologists, the British Association of Urological Surgeons and the National Institute for Health and Care Excellence, we conducted the UK Register of Prostate Embolization (UK-ROPE) study, which recruited 305 patients across 17 UK urological/interventional radiology centres, 216 of whom underwent PAE and 89 of whom underwent TURP. The primary outcomes were International Prostate Symptom Score (IPSS) improvement in the PAE group at 12 months post-procedure, and complication data post-PAE. We also aimed to compare IPSS score improvements between the PAE and TURP groups, using non-inferiority analysis on propensity-score-matched patient pairs. The clinical results and urological measurements were performed at clinical sites. IPSS and other questionnaire-based results were mailed by patients directly to the trial unit managing the study. All data were uploaded centrally to the UK-ROPE study database.

Results: The results showed that PAE was clinically effective, producing a median 10-point IPSS improvement from baseline at 12 months post-procedure. PAE did not appear to be as effective as TURP, which produced a median 15-point IPSS score improvement at 12 months post-procedure. These findings are further supported by the propensity score analysis, in which we formed 65 closely matched pairs of patients who underwent PAE and patients who underwent TURP. In terms of IPSS and quality-of-life (QoL) improvement, there was no evidence of PAE being non-inferior to TURP. Patients in the PAE group had a statistically significant improvement in maximum urinary flow rate and prostate volume reduction at 12 months post-procedure. PAE had a reoperation rate of 5% before 12 months and 15% after 12 months (20% total rate), and a low complication rate. Of 216 patients, one had sepsis, one required a blood transfusion, four had local arterial dissection and four had a groin haematoma. Two patients had non-target embolization that presented as self-limiting penile ulcers. Additional patient-reported outcomes, pain levels and return to normal activities were very encouraging for PAE. Seventy-one percent of PAE cases were performed as outpatient or day cases. In contrast, 80% of TURP cases required at least 1 night of hospital stay, and the majority required 2 nights.

Conclusion: Our results indicate that PAE provides a clinically and statistically significant improvement in symptoms and QoL, although some of these improvements were greater in the TURP arm. The safety profile and quicker return to normal activities may be seen as highly beneficial by patients considering PAE as an alternative treatment to TURP, with the concomitant advantages of reduced length of hospital stay and need for admission after PAE. PAE is an advanced embolization technique demanding a high level of expertise, and should be performed by experienced interventional radiologists who have been trained and proctored appropriately. The use of cone-beam computed tomography is encouraged to improve operator confidence and minimize non-target embolizations. The place of PAE in the care pathway is between that of drugs and surgery, allowing the clinician to tailor treatment to individual patients' symptoms, requirements and anatomical variation.
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http://dx.doi.org/10.1111/bju.14249DOI Listing
August 2018

Body Composition following Necrotising Enterocolitis in Preterm Infants.

Neonatology 2018 23;113(3):242-248. Epub 2018 Jan 23.

Section of Neonatal Medicine, Department of Medicine, Imperial College London, Chelsea and Westminster Campus, London, United Kingdom.

Background: The optimal nutritional regimen for preterm infants, including those that develop necrotising enterocolitis (NEC), is unknown.

Objective: The objective here was to evaluate body composition at term in infants following NEC, in comparison with healthy infants. The primary outcome measure was non-adipose tissue mass (non-ATM).

Methods: We compared body composition assessed by magnetic resonance imaging at term in infants born <31 weeks of gestational age that participated in NEON, a trial comparing incremental versus immediate delivery of parenteral amino acids on non-ATM, and SMOF versus intralipid on intrahepatocellular lipid content. There were no differences in the primary outcomes. We compared infants that received surgery for NEC (NEC-surgical), infants with medically managed NEC (NEC-medical), and infants without NEC (reference).

Results: A total of 133 infants were included (8 NEC-surgical; 15 NEC-medical; 110 reference). In comparison with the reference group, infants in the NEC-surgical and NEC-medical groups were significantly lighter [adjusted mean difference (95% CI) NEC-surgical: -630 g (-1,010, -210), p = 0.003; NEC-medical: -440 g (-760, -110), p = 0.009] and the total adipose tissue volume (ATV) was significantly lower [NEC-surgical: -360 cm3 (-516, -204), p < 0.001; NEC-medical: -127 cm3 (-251, -4); p = 0.043]. There were no significant differences in non-ATM [adjusted mean difference (95% CI) NEC-surgical: -46 g (-281, 189), p = 0.70; NEC-medical: -122 g (-308, 63), p = 0.20].

Conclusion: The lower weight at term in preterm infants following surgically and medically managed NEC, in comparison to preterm infants that did not develop the disease, was secondary to a reduction in ATV. This suggests that the nutritional regimen received was adequate to preserve non-ATM but not to support the normal third-trimester deposition of adipose tissue in preterm infants.
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http://dx.doi.org/10.1159/000485827DOI Listing
September 2019

Should the dilated ascending aorta be repaired at the time of bicuspid aortic valve replacement?

Eur J Cardiothorac Surg 2018 03;53(3):560-568

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Objectives: Bicuspid aortic valve (BAV) is the most common congenital valvular abnormality and frequently presents with accelerated calcific aortic valve disease, requiring aortic valve replacement (AVR) and thoracic aortic aneurysm and dissection. Supporting evidence for Association Guidelines of aortic dimensions for aortic resection is sparse. We sought to determine whether concurrent repair of dilated or aneurysmal aortic disease during AVR in patients with BAV substantially improves morbidity and mortality outcomes.

Methods: Mortality and reoperation outcomes of 1301 adults with BAV and dilated aorta undergoing AVR-only surgery were compared to patients undergoing AVR with aortic resection (AVR-AR) using Cox proportional hazards modelling and patient matching.

Results: Clinically important differences in patient characteristics, aortic valve function and aortic dimensions were identified between cohorts. Event rates were low, with rates of reoperation and death within 1 year of only 1.8% and 5.4%, respectively, and no aortic dissection observed during follow-up. There were no significant differences in reoperation or mortality outcomes between the AVR-only and AVR-AR cohorts. Age, aortic dimension or a combination thereof was not associated with better or worse outcomes after each AVR-AR compared with AVR.

Conclusions: We conclude AVR-only and AVR-AR surgery have low morbidity and mortality and have utility over a wide range of age and aortic sizes. Our results do not provide support for the 45-mm aortic dimension recommended in the current guidelines for aortic resection while performing AVR or any other specific dimension.
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http://dx.doi.org/10.1093/ejcts/ezx387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018902PMC
March 2018

Decision theory for comparing institutions.

Stat Med 2018 02 16;37(3):457-472. Epub 2017 Oct 16.

Department of Medicine, Imperial College, London, UK.

Various forms of performance assessment are applied to public service institutions, such as hospitals, schools, police units, and local authorities. Difficulties arise in the interpretation of the results presented in some established formats because they require a good understanding and appreciation of the uncertainties involved. Usually the results have to be adapted to the perspectives of the users-managers of the assessed units, a consumer, or a central authority (a watchdog) that dispenses awards and sanctions. We present a decision-theoretical approach to these and related problems in which the perspectives are integrated in the analysis and its results are choices from a finite list of options (alternative courses of action).
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http://dx.doi.org/10.1002/sim.7525DOI Listing
February 2018

Variation of the rates of necrotising enterocolitis in the neonatal networks in England.

Stat Med 2017 05 17;36(10):1655-1668. Epub 2017 Feb 17.

Imperial College, London, U.K.

Necrotising enterocolitis is an oft-fatal disease of the intestinal tract in neonates born prematurely and with low birthweight. We study the variation of its rates across the neonatal networks (groups of hospital-based neonatal care units) in England. We illustrate the problematic nature of hypothesis testing for a key decision, which an analysis is meant to inform, and apply an approach based on decision theory. We emphasise the role of sensitivity analysis in dealing with the ambiguity encountered in the process of eliciting information about the perspective of the client or sponsor for whom the analysis is conducted. In the application based on a fiducial distribution, the likelihood is approximated by a linearising transformation of the score function. Copyright © 2017 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/sim.7249DOI Listing
May 2017

Duration of Postoperative Atrial Fibrillation After Cardiac Surgery Is Associated With Worsened Long-Term Survival.

Ann Thorac Surg 2016 Dec 15;102(6):2018-2026. Epub 2016 Jul 15.

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: Studies of the effects of postoperative atrial fibrillation (poAF) on long-term survival are conflicting, likely because of comorbidities that occur with poAF and the patient populations studied. Furthermore, the effects of poAF duration on long-term survival are poorly understood.

Methods: We utilized a prospectively collected database on outcomes of cardiac surgery at a large tertiary care institution between August 2001 and December 2010 with survival follow-up through June 2015 to analyze long-term survival of patients with poAF. In addition, we identified patient- and procedure-related variables associated with poAF, and estimated overall comorbidity burden using the Elixhauser comorbidity index. Survival was compared between patients with poAF (n = 513) and a propensity score matched control cohort, both for all patients and separately for subgroups of patients with poAF lasting less than 2 days (n = 218) and patients with prolonged poAF (n = 265).

Results: Patients with poAF were older and had a higher burden of comorbidities. Survival was significantly worse for patients with poAF than for the matched control group (hazard ratio 1.43, 95% confidence interval: 1.11 to 1.86). That was driven by decreased survival among patients with prolonged poAF (hazard ratio 1.97, 95% confidence interval: 1.37 to 2.80), whereas survival of patients with poAF for less than 2 days was not significantly different from that of matched controls (hazard ratio 0.91, 95% confidence interval: 0.60 to 1.39).

Conclusions: After close matching based on comorbidity burden, prolonged poAF is still associated with decreased survival. Therefore, vigilance is warranted in monitoring and treating patients with prolonged poAF after cardiac surgery.
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http://dx.doi.org/10.1016/j.athoracsur.2016.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506267PMC
December 2016

Comparing two treatments by decision theory.

Pharm Stat 2016 09 1;15(5):387-95. Epub 2016 Jun 1.

Department of Medicine, Imperial College, London, UK.

Decision theory is applied to the general problem of comparing two treatments in an experiment with subjects assigned to the treatments at random. The inferential agenda covers collection of evidence about superiority, non-inferiority and average bioequivalence of the treatments. The proposed approach requires defining the terms 'small' and 'large' to qualify the magnitude of the treatment effect and specifying the losses (or loss functions) that quantify the consequences of the incorrect conclusions. We argue that any analysis that ignores these two inputs is deficient, and so is any ad hoc way of taking them into account. Sample size calculation for studies intended to be analysed by this approach is also discussed. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/pst.1754DOI Listing
September 2016

Classification in two-stage screening.

Stat Med 2015 Nov 16;34(25):3281-97. Epub 2015 Jun 16.

SNTL and UPF, Barcelona, Spain.

Decision theory is applied to the problem of setting thresholds in medical screening when it is organised in two stages. In the first stage that involves a less expensive procedure that can be applied on a mass scale, an individual is classified as a negative or a likely positive. In the second stage, the likely positives are subjected to another test that classifies them as (definite) positives or negatives. The second-stage test is more accurate, but also more expensive and more involved, and so there are incentives to restrict its application. Robustness of the method with respect to the parameters, some of which have to be set by elicitation, is assessed by sensitivity analysis.
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http://dx.doi.org/10.1002/sim.6554DOI Listing
November 2015

Survey of the clinical assessment and utility of near-infrared cerebral oximetry in cardiac surgery.

J Cardiothorac Vasc Anesth 2014 Apr 17;28(2):308-16. Epub 2013 Oct 17.

SNTL Statistics Research and Consulting, Barcelona, Spain.

Objectives: Near-infrared cerebral oximetry increasingly is used for monitoring during cardiac surgery. Nonetheless, the scientific basis for incorporating this technology into clinical practice, the indications for when to do so, and standard diagnostic and treatment algorithms for defining abnormal values are yet to be rigorously defined. The authors hypothesized that there would be (1) variation in clinical use and practices for near-infrared spectroscopy (NIRS), and (2) variation in management of patients when clinicians are provided with NIRS information. In order to test this hypothesis, they sought to assess the nature and strength of response heterogeneity among anesthesiologists and cardiac perfusionists when provided with cardiac surgery patient scenarios and cerebral oximetry data.

Design: A prospectively collected survey.

Setting: A hospital-based, multi-institutional, multinational study.

Participants: By e-mail, the authors surveyed the membership of the Society of Cardiovascular Anesthesiologists and the online Cardiovascular Perfusion Forum.

Interventions: This survey was focused on ascertaining what actions clinicians would take in each scenario, given case information and cerebral oximetry tracings. Questions were based on 11 patient scenarios selected to represent small, large, symmetric, or asymmetric decreases in measured regional cerebral oxygen saturation (rScO2) encountered during cardiac surgery. Information on the respondents' (n = 796; 73% anesthesiologists) clinical practice, demography, and cerebral oximetry utilization was collected. An index of dispersion was used to assess response heterogeneity overall and within demographic subgroups.

Measurements And Main Results: The majority of respondents indicated that cerebral oximetry monitoring was either useful or an essential monitor, especially perfusionists and clinicians who used cerebral oximetry most frequently. There were marked differences in responses between perfusionists and anesthesiologists for 4 of the 6 scenarios (p<0.005 for each of these 4 scenarios) occurring during cardiopulmonary bypass. Scenarios having greatest rScO2 reduction or asymmetry in rScO2 were associated with the highest dispersion, indicating least agreement in management. Scenarios with mild or moderate rScO2 reduction were associated with the lowest dispersion, indicating greater agreement in management.

Conclusions: Although experimental data gradually are accumulating to support the role for cerebral oximetry monitoring during cardiac surgery, the results of the present survey support the view that its role remains poorly defined, and consensus for its appropriate use is lacking. Importantly, the authors observed marked variation in the use, perceived utility, and management of patients for 4 of the 6 CPB scenarios between perfusionists and anesthesiologists who share the management of CPB. These findings support the need for well-designed, adequately-powered clinical trials examining the value of this technology.
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http://dx.doi.org/10.1053/j.jvca.2013.06.003DOI Listing
April 2014

A decision-theoretical alternative to testing many hypotheses.

Biostatistics 2014 Jan 27;15(1):154-69. Epub 2013 Aug 27.

SNTL and Universitat Pompeu Fabra, Ramon Trias Fargas 25-27, 08005 Barcelona, Spain.

Testing a large number of hypotheses is a key problem in the analysis of microarray experiments and in other studies in which many elementary experiments are conducted, and the exceptions among them, for which a particular hypothesis does not hold, have to be identified. A class of approaches to this problem is based on controlling the false discovery rate, even though failure to discover should also be considered. We develop a decision-theoretical approach in which errors (misclassifications) of the two kinds are associated with uneven losses, and the total expected loss in the collection of the classifications (decisions made or options selected) is minimized.
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http://dx.doi.org/10.1093/biostatistics/kxt030DOI Listing
January 2014

Screening as an application of decision theory.

Stat Med 2013 Feb 17;32(5):849-63. Epub 2012 Aug 17.

SNTL and UPF, Barcelona, Spain.

We develop a decision-theoretical approach to setting the threshold for a screening procedure that declares each examined subject as a positive or a negative. It is fundamentally different from maximising the Youden index. The method incorporates the consequences of the two kinds of bad decisions (false positives and false negatives) by means of a set of plausible loss functions elicited from a subject-matter expert or committee. We present details for several classes of loss functions and within-group distributions of the outcomes. We outline extensions related to mixture distributions and compositions of loss functions. We illustrate the method on simulated examples and apply it to real datasets.
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http://dx.doi.org/10.1002/sim.5554DOI Listing
February 2013

Handling the limit of detection by extrapolation.

Stat Med 2012 Nov 25;31(26):3133-46. Epub 2012 Apr 25.

SNTL and UPF, Barcelona, Spain.

A general method of estimation with a variable observed subject to a limit of detection is introduced. It is based on extrapolation of the estimates obtained by increasing the limit of detection. Theoretical arguments support the method in some special cases, and it is explored by simulations. Several examples are presented and adaptations for other kinds of censoring explored.
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http://dx.doi.org/10.1002/sim.5373DOI Listing
November 2012

Estimation of the effect size in meta-analysis with few studies.

Stat Med 2010 Feb;29(4):421-30

SNTL and Departament d'Economia i Empresa, Universitat Pompeu Fabra, Barcelona, Spain.

Meta-analysis is often conducted with only a small number of studies. Adjustments of the (restricted) maximum likelihood estimator of the effect size are derived and their gains in efficiency are explored. The proposed estimators are applied to three sets of studies.
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http://dx.doi.org/10.1002/sim.3814DOI Listing
February 2010

On selection and composition in small area and mapping problems.

Stat Methods Med Res 2005 Feb;14(1):3-16

Institute of Information Science and Technology, Massey University, Palmerston North, New Zealand.

Maps in which small areas, such as districts, are represented by colours, shades or symbols with sizes determined by the values of estimates are regarded as an indispensable graphical output of analyses concerned with the geographical detail of economic, social, ecological and epidemiological phenomena. The distortion of the distribution of the district specific quantities in such maps, due to misrepresentation of the uncertainty about the estimated values, is discussed, and an alternative based on drawing so-called plausible maps is described. We highlight the pervasive and nonignorable nature of the selection process that identifies the quantity (target) to be estimated. A problem specific to disease mapping is what action, often one of a discrete set, to take in response to the results of an analysis. We argue that the costs (values) associated with correct and incorrect decisions should be integrated in the analysis and, when an analytical treatment is not feasible, plausible scenarios played out by simulations.
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http://dx.doi.org/10.1191/0962280205sm385oaDOI Listing
February 2005
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