Publications by authors named "Ed Juszczak"

24 Publications

  • Page 1 of 1

Parental experiences of being approached to join multiple neonatal clinical trials: qualitative study (PARENT).

Arch Dis Child Fetal Neonatal Ed 2021 Jan 31;106(1):84-87. Epub 2020 Jul 31.

Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK

Objective: To explore parents' perceptions and experience of being approached for enrolment of their preterm infant in more than one trial or study.

Design: A qualitative study involving 17 in-depth semistructured interviews, with parents who had been approached for multiple studies and who subsequently consented for their infant(s) to join at least one. Parents who declined all studies were not approached.

Setting And Participants: Parents of preterm infants receiving care at one of three neonatal intensive care units in the north of England.

Findings: Most parents did not view concurrent participation in multiple trials or studies as a significant issue within the wider context of their infant's care. Most parents did not feel pressured into enrolling their infant into more than one study, but some suggested that participation in several provided justification for the subsequent refusal to join others, articulating feeling of guilt at saying 'no', and others appeared fatigued by multiple approaches. Parents focused on the perceived risks and benefits of each individual study and, while acknowledging that making a fully informed decision was not possible, largely agreed due to their belief in the benefits of research, trust in the health professionals caring for their baby and a range of complex personal motivations.

Conclusions: Parents valued the autonomy to make decisions about participation and felt, with hindsight, that their decisions were right. Research teams could be more aware of parental feelings of guilt or gratitude that may motivate them to give consent. Similarly, the capacity of parents to fully remember details of multiple studies when they are stressed, and their infant is sick, should be taken into consideration, and continued efforts should be made to ensure ongoing consent to participation.
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January 2021

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

Arch Dis Child Fetal Neonatal Ed 2020 Nov 2;105(6):587-592. Epub 2020 Apr 2.

Health Economics Unit, Institute of Applied Health Research, University of Birmingham, Birmingham, UK

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.
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November 2020

The WHEAT pilot trial-WithHolding Enteral feeds Around packed red cell Transfusion to prevent necrotising enterocolitis in preterm neonates: a multicentre, electronic patient record (EPR), randomised controlled point-of-care pilot trial.

BMJ Open 2019 09 20;9(9):e033543. Epub 2019 Sep 20.

Clinical Trials Unit, Nuffield Department of Population Health, University of Oxford, National Perinatal Epidemiology Unit, Oxford, UK.

Introduction: Necrotising enterocolitis (NEC) is a potentially devastating neonatal disease. A temporal association between red cell transfusion and NEC is well described. Observational data suggest that withholding enteral feeds around red cell transfusions may reduce the risk of NEC but this has not been tested in randomised trials; current UK practice varies. Prevention of NEC is a research priority but no appropriately powered trials have addressed this question. The use of a simplified opt-out consent model and embedding trial processes within existing electronic patient record (EPR) systems provide opportunities to increase trial efficiency and recruitment.

Methods And Analysis: We will undertake a randomised, controlled, multicentre, unblinded, pilot trial comparing two care pathways: continuing milk feeds (before, during and after red cell transfusions) and withholding milk feeds (for 4 hours before, during and for 4 hours after red cell transfusions), with infants randomly assigned with equal probability. We will use opt-out consent. A nested qualitative study will explore parent and health professional views. Infants will be eligible if born at <30+0 gestational weeks+days. Primary feasibility outcomes will be rate of recruitment, opt-out, retention, compliance, data completeness and data accuracy; clinical outcomes will include mortality and NEC. The trial will recruit in two neonatal networks in England for 9 months. Data collection will continue until all infants have reached 40+0 corrected gestational weeks or neonatal discharge. Participant identification and recruitment, randomisation and all trial data collection will be embedded within existing neonatal EPR systems (BadgerNet and BadgerEPR); outcome data will be extracted from routinely recorded data held in the National Neonatal Research Database.

Ethics And Dissemination: This study holds Research Ethics Committee approval to use an opt-out approach to consent. Results will inform future EPR-embedded and data-enabled trials and will be disseminated through conferences, publications and parent-centred information.

Trial Registration Number: ISRCTN registry ISRCTN62501859; Pre-results.
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September 2019

Safety and efficacy of 2% chlorhexidine gluconate aqueous versus 2% chlorhexidine gluconate in 70% isopropyl alcohol for skin disinfection prior to percutaneous central venous catheter insertion in preterm neonates: the ARCTIC randomised-controlled feasibility trial protocol.

BMJ Open 2019 02 19;9(2):e028022. Epub 2019 Feb 19.

Paediatric Infectious Diseases Research Group, Infection and Immunity, St George's University of London, London, UK.

Introduction: Catheter-related sepsis is one of the most dangerous complications of neonatal intensive care and is associated with significant morbidity and mortality. Use of catheter-care 'bundles' has reduced the incidence of catheter-related sepsis, although individual components have not been well studied. Better evidence is needed to guide selection of the most appropriate antiseptic solution for skin disinfection in preterm neonates. This study will inform the feasibility and design of the first randomised controlled trial to examine the safety and efficacy of alcohol-based versus aqueous-based chlorhexidine antiseptic formulations for skin disinfection prior to percutaneous central venous catheterisation in preterm neonates. The antiseptics to be compared are 2% chlorhexidine gluconate (CHG) aqueous and 2% CHG in 70% isopropyl alcohol.

Methods And Analysis: The Antiseptic Randomised Controlled Trial for Insertion of Catheters (ARCTIC) is a two-centre randomised-controlled feasibility trial. At least 100 preterm infants born at <34 weeks' gestation and due to undergo percutaneous insertion of a central venous catheter will be randomly allocated to receive prior skin disinfection with one of the two antiseptic solutions. Outcomes include: i) recruitment and retention rates; ii) completeness of data collection; iii) numbers of enrolled infants meeting case definitions for definite catheter-related sepsis, catheter-associated sepsis and catheter colonisation and iv) safety outcomes of skin morbidity scores recorded daily from catheter insertion until 48 hours post removal. The key feasibility metrics will be reported as proportions with 95% CIs. Estimated prevalence of catheter colonisation will allow calculation of sample size for the large-scale trial. The data will inform whether it will be feasible to progress to a large-scale trial.

Ethics And Dissemination: ARCTIC has been approved by the National Health Service Health Research Authority National Research Ethics Service Committee East of England (Cambridge South) (IRAS ID 163868), was adopted onto the National Institute of Health Research Clinical Research Network portfolio (CPMS ID 19899) and is registered with an International Standard Randomised Control Trials Number (ISRCTN: 82571474; Pre-results) and European Clinical Trials Database number 2015-000874-36. Dissemination plans include presentations at scientific conferences, scientific publications and sharing of the findings with parents via the support of Bliss baby charity.

Trial Registration Number: ISRCTN82571474; Pre-results.
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February 2019

Prophylactic antibiotics for the prevention of infection following operative vaginal delivery (ANODE): study protocol for a randomised controlled trial.

Trials 2018 Jul 24;19(1):395. Epub 2018 Jul 24.

National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK.

Background: Sepsis is one of the most important causes of maternal death and severe morbidity worldwide. Studies conducted both in the UK and US have documented an additional risk associated with operative vaginal delivery. However, a Cochrane review, updated in 2017, identified only one small trial of prophylactic antibiotics following operative vaginal delivery, which included a total of 393 women. Given the small size of that trial, it recommended that further robust evidence is needed. Operative vaginal delivery rates vary worldwide, but typically 5-10% of women have operative vaginal births. A conservative estimated incidence of maternal infection following operative vaginal delivery is 4%, based on the one previous trial. There is, therefore, considerable scope for direct patient benefit from an effective preventive strategy.

Methods/design: This protocol describes a multicentre, randomised, blinded, placebo-controlled trial aiming to recruit 3424 participants from over 20 hospital sites in the UK. Women who have undergone an operative vaginal delivery at 36 weeks or greater gestation with no indication for ongoing antibiotics in the postpartum period and no contra-indications to prophylactic co-amoxiclav, will be randomised to receive a single intravenous dose of co-amoxiclav or placebo. The primary outcome will be confirmed or suspected maternal infection within 6 weeks of delivery, as defined by one of (a) a new prescription of antibiotics for presumed perineal wound-related infection, endometritis or uterine infection, urinary tract infection with systemic features or other systemic infection, (b) systemic infection confirmed with a culture or (c) endometritis as defined by the US Centers for Disease Control and Prevention. Outcome information will be collected by a single telephone interview and questionnaire, with clinical data collected from medical records or the hospital laboratory if necessary, at 6 weeks post-delivery.

Discussion: This randomised trial will investigate whether a prophylactic dose of antibiotic following operative vaginal delivery can reduce the incidence of infection and sepsis. If shown to be effective, this could lead to a change in recommended practice and the prevention of infection. Conversely, if there is no significant difference between the two arms, then this could contribute to a reduction in antibiotic use and improved antimicrobial stewardship.

Trial Registration: ISRCTN11166984 . Registered on 23 September 2015.
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July 2018

Glibenclamide and metfoRmin versus stAndard care in gEstational diabeteS (GRACES): a feasibility open label randomised trial.

BMC Pregnancy Childbirth 2017 Sep 22;17(1):316. Epub 2017 Sep 22.

Tommy's Centre for Maternal and Fetal Health Research, Medical Research Council Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.

Background: Metformin is widely used to treat gestational diabetes (GDM), but many women remain hyperglycaemic and require additional therapy. We aimed to determine recruitment rate and participant throughput in a randomised trial of glibenclamide compared with standard therapy insulin (added to maximum tolerated metformin) for treatment of GDM.

Methods: We conducted an open label feasibility study in 5 UK antenatal clinics among pregnant women 16 to 36 weeks' gestation with metformin-treated GDM. Women failing to achieve adequate glycaemic control on metformin monotherapy were randomised to additional glibenclamide or insulin. The primary outcome was recruitment rate. We explored feasibility with uptake, retention, adherence, safety, glycaemic control, participant satisfaction and clinical outcomes.

Results: Records of 197 women were screened and 23 women randomised to metformin and glibenclamide (n = 13) or metformin and insulin (n = 10). Mean (SD) recruitment rate was 0.39 (0.62) women/centre/month. 9/13 (69.2%, 95%CI 38.6-90.9%) women adhered to glibenclamide and all provided outcome data (100% retention). There were no episodes of severe hypoglycaemia, but metformin and insulin gave superior glycaemic control to metformin and glibenclamide, with fewer blood glucose readings <3.5 mmol/l (median [IQR] difference/woman/week of treatment 0.58 [0.03-1.87]).

Conclusions: A large randomised controlled trial comparing glibenclamide or insulin in combination with metformin for women with GDM would be feasible but is unlikely to be worthwhile, given the poorer glycaemic control with glibenclamide and metformin in this pilot study. The combination of metformin and glibenclamide should be reserved for women with GDM with true needle phobia or inability to use insulin therapy.

Trial Registration: registration number:NCT02080377 February 11th 2014.
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September 2017

A blinded randomised placebo-controlled trial investigating the efficacy of morphine analgesia for procedural pain in infants: Trial protocol.

Wellcome Open Res 2016 Nov 15;1. Epub 2016 Nov 15.

Department of Paediatrics, University of Oxford, Oxford, UK.

Infant pain has both immediate and long-term negative consequences, yet in clinical practice it is often undertreated. To date, few pain-relieving drugs have been tested in infants. Morphine is a potent analgesic that provides effective pain relief in adults, but there is inconclusive evidence for its effectiveness in infants. The purpose of this study is to establish whether oral morphine provides effective analgesia for procedural pain in infants. A blinded, placebo-controlled, parallel-group randomized, phase II, clinical trial will be undertaken to determine whether morphine sulphate administered orally prior to clinically-required retinopathy of prematurity (ROP) screening and heel lancing provides effective analgesia. 
156 infants between 34 and 42 weeks' gestational age who require a clinical heel lance and ROP screening on the same test occasion will be included in the trial. Infants will be randomised to receive either a single dose of morphine sulphate (100 μg/kg) or placebo. Each infant will be monitored for 48 hours and safety data will be collected during the 24 hours following drug administration. The primary outcome will be the Premature Infant Pain Profile-revised (PIPP-R) score 30 seconds after ROP screening. The co-primary outcome will be the magnitude of nociceptive-specific brain activity evoked by a clinically-required heel lance. Infant clinical stability will be assessed by comparing the number of episodes of bradycardia, tachycardia, desaturation and apnoea, and changes in respiratory support requirements in the 24-hour periods before and after the clinical intervention. In addition, drug safety will be assessed by considering the occurrence of apnoeic and hypotensive episodes requiring intervention in the 24-hour period following drug administration. This study has been published as an by .
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November 2016

Compression stockings for preventing deep vein thrombosis in airline passengers.

Cochrane Database Syst Rev 2016 Sep 14;9:CD004002. Epub 2016 Sep 14.

Centre for Public Health, Queen's University Belfast, Institute of Clinical Sciences, Block B, Royal Victoria Hospital, Grosvenor Road, Belfast, Northern Ireland, UK, BT12 6BJ.

Background: Air travel might increase the risk of deep vein thrombosis (DVT). It has been suggested that wearing compression stockings might reduce this risk. This is an update of the review first published in 2006.

Objectives: To assess the effects of wearing compression stockings versus not wearing them for preventing DVT in people travelling on flights lasting at least four hours.

Search Methods: For this update the Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (10 February 2016). In addition, the CIS searched the Cochrane Register of Studies (CENTRAL (2016, Issue 1)).

Selection Criteria: Randomised trials of compression stockings versus no stockings in passengers on flights lasting at least four hours. Trials in which passengers wore a stocking on one leg but not the other, or those comparing stockings and another intervention were also eligible.

Data Collection And Analysis: Two review authors independently selected trials for inclusion and extracted data. We sought additional information from trialists where necessary.

Main Results: One new study that fulfilled the inclusion criteria was identified for this update. Eleven randomised trials (n = 2906) were included in this review: nine (n = 2821) compared wearing graduated compression stockings on both legs versus not wearing them; one trial (n = 50) compared wearing graduated compression tights versus not wearing them; and one trial (n = 35) compared wearing a graduated compression stocking on one leg for the outbound flight and on the other leg on the return flight. Eight trials included people judged to be at low or medium risk of developing DVT (n = 1598) and two included high-risk participants (n = 1273). All flights had a duration of more than five hours.Fifty of 2637 participants with follow-up data available in the trials of wearing compression stockings on both legs had a symptomless DVT; three wore stockings, 47 did not (odds ratio (OR) 0.10, 95% confidence interval (CI) 0.04 to 0.25, P < 0.001; high-quality evidence). There were no symptomless DVTs in three trials. Sixteen of 1804 people developed superficial vein thrombosis, four wore stockings, 12 did not (OR 0.45, 95% CI 0.18 to 1.13, P = 0.09; moderate-quality evidence). No deaths, pulmonary emboli or symptomatic DVTs were reported. Wearing stockings had a significant impact in reducing oedema (mean difference (MD) -4.72, 95% CI -4.91 to -4.52; based on six trials; low-quality evidence). A further two trials showed reduced oedema in the stockings group but could not be included in the meta-analysis as they used different methods to measure oedema. No significant adverse effects were reported.

Authors' Conclusions: There is high-quality evidence that airline passengers similar to those in this review can expect a substantial reduction in the incidence of symptomless DVT and low-quality evidence that leg oedema is reduced if they wear compression stockings. Quality was limited by the way that oedema was measured. There is moderate-quality evidence that superficial vein thrombosis may be reduced if passengers wear compression stockings. We cannot assess the effect of wearing stockings on death, pulmonary embolism or symptomatic DVT because no such events occurred in these trials. Randomised trials to assess these outcomes would need to include a very large number of people.
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September 2016

ESBL-producing Enterobacteriaceae in 24 neonatal units and associated networks in the south of England: no clustering of ESBL-producing Escherichia coli in units or networks.

J Antimicrob Chemother 2016 May 10;71(5):1174-7. Epub 2016 Jan 10.

Blizard Institute, Queen Mary, University of London, London, UK.

Objectives: The objectives of this study were to characterize ESBL-producing Enterobacteriaceae present in 24 neonatal units (NNUs) in eight networks participating in a multicentre probiotic study and to test the hypothesis that specific strains would cluster within individual units and networks.

Methods: We performed analysis of stool samples for the presence of ESBL-producing Enterobacteriaceae at 2 weeks post-natal age and 36 weeks post-menstrual age. ESBL-producing Enterobacteriaceae were characterized and typed using molecular methods.

Results: ESBL-producing Enterobacteriaceae (n = 71) were isolated from 67/1229 (5.5%) infants from whom we received a sample at either sampling time or both sampling times, and from infants in 18 (75%) of the 24 recruiting NNUs. Thirty-three Escherichia coli, 23 Klebsiella spp. and 6 Enterobacter spp. strains were characterized. ESBL-producing E. coli were all distinguishable within individual NNUs by antibiotic resistance genotype, serogroup (O25b), phenotype, phylotype or ST. Ten of the 33 were ST131 and 9 of the 10 ST131 isolates were ciprofloxacin resistant. Seven of the 10 ST131 isolates carried genes encoding CTX-M group 1 enzymes. ST131 isolates were isolated from centres within five of the eight NNU networks. There were clusters of indistinguishable ESBL-producing Klebsiella and Enterobacter isolates associated with specific NNUs.

Conclusions: Strains of E. coli ST131 were distributed across neonatal networks in the south of England. There was no evidence of clustering of clonally related ESBL-producing E. coli strains, by contrast with Klebsiella spp. and Enterobacter spp., which did cluster within units. The possibility that ESBL-producing E. coli strains are spread by vertical transmission requires further investigation.
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May 2016

CORONIS - International study of caesarean section surgical techniques: the follow-up study.

BMC Pregnancy Childbirth 2013 Nov 21;13:215. Epub 2013 Nov 21.

Background: The CORONIS Trial was a 2×2×2×2×2 non-regular, fractional, factorial trial of five pairs of alternative caesarean section surgical techniques on a range of short-term outcomes, the primary outcome being a composite of maternal death or infectious morbidity. The consequences of different surgical techniques on longer term outcomes have not been well assessed in previous studies. Such outcomes include those related to subsequent pregnancy: mode of delivery; abnormal placentation (e.g. accreta); postpartum hysterectomy, as well as longer term pelvic problems: pain, urinary problems, infertility. The Coronis Follow-up Study aims to measure and compare the incidence of these outcomes between the randomised groups at around three years after women participated in the CORONIS Trial.

Methods/design: This study will assess the following null hypotheses: In women who underwent delivery by caesarean section, no differences will be detected with respect to a range of long-term outcomes when comparing the following five pairs of alternative surgical techniques evaluated in the CORONIS Trial: 1. Blunt versus sharp abdominal entry. 2. Exteriorisation of the uterus for repair versus intra-abdominal repair. 3. Single versus double layer closure of the uterus. 4. Closure versus non-closure of the peritoneum (pelvic and parietal). 5. Chromic catgut versus Polyglactin-910 for uterine repair. The outcomes will include (1) women's health: pelvic pain; dysmenorrhoea; deep dyspareunia; urinary symptoms; laparoscopy; hysterectomy; tubal/ovarian surgery; abdominal hernias; bowel obstruction; infertility; death. (2) Outcomes of subsequent pregnancies: inter-pregnancy interval; pregnancy outcome; gestation at delivery; mode of delivery; pregnancy complications; surgery during or following delivery.

Discussion: The results of this follow-up study will have importance for all pregnant women and for health professionals who provide care for pregnant women. Although the results will have been collected in seven countries with limited health care resources (Argentina, Chile, Ghana, India, Kenya, Pakistan, Sudan) any differences in outcomes associated with different surgical techniques are likely to be generalisable throughout the world.

Trial Registration: ISRCTN31089967.
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November 2013

Neonatal ECMO study of temperature (NEST): a randomized controlled trial.

Pediatrics 2013 Nov 21;132(5):e1247-56. Epub 2013 Oct 21.

DM, Department of Health Sciences, University of Leicester, 22-28 Princess Rd West, Leicester, UK.

Background: Despite evidence to support the use of extracorporeal membrane oxygenation (ECMO) in defined groups of newborn infants, rates of impairment among survivors remain high. Therapeutic hypothermia has been shown to provide neuroprotection in mature infants exposed to perinatal asphyxia. We hypothesized that therapeutic hypothermia during ECMO would reduce the proportion of infants with brain injury, and thus later impairment.

Methods: We conducted a randomized trial in the United Kingdom to compare ECMO with cooling (34°C for the first 48 to 72 hours) with standard ECMO (37°C). The primary outcome was the cognitive composite score of the Bayley Scales of Infant and Toddler Development, 3rd edition, at 2 years. Prespecified secondary outcomes included death, neonatal morbidity, and other neurodevelopmental and behavioral outcomes at 2 years.

Results: A total of 111 infants were entered into the study, 14 died before 2 years of age (16% who received ECMO with cooling vs 9% who received ECMO alone). Two infants were lost to follow-up, and 8 were unable to complete the full range of tests. For 45 evaluated infants who received ECMO with cooling, mean cognitive scores at 2 years were 88.0 (SD: 16.2) compared with 90.6 (SD: 13.1) for 48 infants receiving ECMO only (difference in means: -2.6; 95% confidence interval: -8.7 to 3.4). The various secondary outcomes were not significantly different between the groups, but most favored ECMO without cooling.

Conclusions: In newborn infants treated by ECMO, the use of mild hypothermia for the first 48 to 72 hours did not result in improved outcomes up to 2 years of age.
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November 2013

Oxygen targeting in preterm infants using the Masimo SET Radical pulse oximeter.

Arch Dis Child Fetal Neonatal Ed 2011 Nov 6;96(6):F429-33. Epub 2011 Mar 6.

Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, UK.

Background: A pretrial clinical improvement project for the BOOST-II UK trial of oxygen saturation targeting revealed an artefact affecting saturation profiles obtained from the Masimo Set Radical pulse oximeter.

Methods: Saturation was recorded every 10 s for up to 2 weeks in 176 oxygen dependent preterm infants in 35 UK and Irish neonatal units between August 2006 and April 2009 using Masimo SET Radical pulse oximeters. Frequency distributions of % time at each saturation were plotted. An artefact affecting the saturation distribution was found to be attributable to the oximeter's internal calibration algorithm. Revised software was installed and saturation distributions obtained were compared with four other current oximeters in paired studies.

Results: There was a reduction in saturation values of 87-90%. Values above 87% were elevated by up to 2%, giving a relative excess of higher values. The software revision eliminated this, improving the distribution of saturation values. In paired comparisons with four current commercially available oximeters, Masimo oximeters with the revised software returned similar saturation distributions.

Conclusions: A characteristic of the software algorithm reduces the frequency of saturations of 87-90% and increases the frequency of higher values returned by the Masimo SET Radical pulse oximeter. This effect, which remains within the recommended standards for accuracy, is removed by installing revised software (board firmware V4.8 or higher). Because this observation is likely to influence oxygen targeting, it should be considered in the analysis of the oxygen trial results to maximise their generalisability.
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November 2011

Randomised controlled double-blind non-inferiority trial of two antivenoms for saw-scaled or carpet viper (Echis ocellatus) envenoming in Nigeria.

PLoS Negl Trop Dis 2010 Jul 27;4(7):e767. Epub 2010 Jul 27.

Department of Community Medicine, Bayero University of Kano, Kano, Nigeria.

Background: In West Africa, envenoming by saw-scaled or carpet vipers (Echis ocellatus) causes great morbidity and mortality, but there is a crisis in supply of effective and affordable antivenom (ISRCTN01257358).

Methods: In a randomised, double-blind, controlled, non-inferiority trial, "EchiTAb Plus-ICP" (ET-Plus) equine antivenom made by Instituto Clodomiro Picado was compared to "EchiTAb G" (ET-G) ovine antivenom made by MicroPharm, which is the standard of care in Nigeria and was developed from the original EchiTAb-Fab introduced in 1998. Both are caprylic acid purified whole IgG antivenoms. ET-G is monospecific for Echis ocellatus antivenom (initial dose 1 vial) and ET-Plus is polyspecific for E. ocellatus, Naja nigricollis and Bitis arietans (initial dose 3 vials). Both had been screened by pre-clinical and preliminary clinical dose-finding and safety studies. Patients who presented with incoagulable blood, indicative of systemic envenoming by E. ocellatus, were recruited in Kaltungo, north-eastern Nigeria. Those eligible and consenting were randomly allocated with equal probability to receive ET-Plus or ET-G. The primary outcome was permanent restoration of blood coagulability 6 hours after the start of treatment, assessed by a simple whole blood clotting test repeated 6, 12, 18, 24 and 48 hr after treatment. Secondary (safety) outcomes were the incidences of anaphylactic, pyrogenic and late serum sickness-type antivenom reactions.

Findings: Initial doses permanently restored blood coagulability at 6 hours in 161/194 (83.0%) of ET-Plus and 156/206 (75.7%) of ET-G treated patients (Relative Risk [RR] 1.10 one-sided 95% CI lower limit 1.01; P = 0.05). ET-Plus caused early reactions on more occasions than did ET-G [50/194 (25.8%) and 39/206 (18.9%) respectively RR (1.36 one-sided 95% CI 1.86 upper limit; P = 0.06). These reactions were classified as severe in 21 (10.8%) and 11 (5.3%) of patients, respectively.

Conclusion: At these doses, ET-Plus was slightly more effective but ET-G was slightly safer. Both are recommended for treating E. ocellatus envenoming in Nigeria.

Trial Registration: Current Controlled Trials ISRCTN01257358.
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July 2010

Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial.

Lancet 2010 Jan 19;375(9712):385-95. Epub 2010 Jan 19.

Oxford Clinical Trials Unit for Mental Illness, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK.

Background: Lithium carbonate and valproate semisodium are both recommended as monotherapy for prevention of relapse in bipolar disorder, but are not individually fully effective in many patients. If combination therapy with both agents is better than monotherapy, many relapses and consequent disability could be avoided. We aimed to establish whether lithium plus valproate was better than monotherapy with either drug alone for relapse prevention in bipolar I disorder.

Methods: 330 patients aged 16 years and older with bipolar I disorder from 41 sites in the UK, France, USA, and Italy were randomly allocated to open-label lithium monotherapy (plasma concentration 0.4-1.0 mmol/L, n=110), valproate monotherapy (750-1250 mg, n=110), or both agents in combination (n=110), after an active run-in of 4-8 weeks on the combination. Randomisation was by computer program, and investigators and participants were informed of treatment allocation. All outcome events were considered by the trial management team, who were masked to treatment assignment. Participants were followed up for up to 24 months. The primary outcome was initiation of new intervention for an emergent mood episode, which was compared between groups by Cox regression. Analysis was by intention to treat. This study is registered, number ISRCTN 55261332.

Findings: 59 (54%) of 110 people in the combination therapy group, 65 (59%) of 110 in the lithium group, and 76 (69%) of 110 in the valproate group had a primary outcome event during follow-up. Hazard ratios for the primary outcome were 0.59 (95% CI 0.42-0.83, p=0.0023) for combination therapy versus valproate, 0.82 (0.58-1.17, p=0.27) for combination therapy versus lithium, and 0.71 (0.51-1.00, p=0.0472) for lithium versus valproate. 16 participants had serious adverse events after randomisation: seven receiving valproate monotherapy (three deaths); five lithium monotherapy (two deaths); and four combination therapy (one death).

Interpretation: For people with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy. This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy.

Funding: Stanley Medical Research Institute; Sanofi-Aventis.
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January 2010

DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer's disease - a multicentre RCT.

Trials 2009 Jul 24;10:57. Epub 2009 Jul 24.

Section of Old Age Psychiatry, The University of Nottingham, A Floor, South Block, Queen's Medical Centre, Nottingham NG7 2UH, UK.

Background: Alzheimer's disease (AD) is the commonest cause of dementia. Cholinesterase inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not recommended by the England and Wales National Institute for Health and Clinical Excellence. However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in particular, what to do as the condition progresses from moderate to severe. Options include continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to establish the most effective drug option for people with AD who are progressing from moderate to severe dementia despite treatment with donepezil.

Method: DOMINO-AD is a pragmatic, 15 centre, double-blind, randomized, placebo controlled trial. Patients with AD, currently living at home, receiving donepezil 10 mg daily, and with Standardized Mini-Mental State Examination (SMMSE) scores between 5 and 13 are being recruited. Each is randomized to one of four treatment options: continuation of donepezil with memantine placebo added; switch to memantine with donepezil placebo added; donepezil and memantine together; or donepezil placebo with memantine placebo. 800 participants are being recruited and treatment continues for one year. Primary outcome measures are cognition (SMMSE) and activities of daily living (Bristol Activities of Daily Living Scale). Secondary outcomes are non-cognitive dementia symptoms (Neuropsychiatric Inventory), health related quality of life (EQ-5D and DEMQOL-proxy), carer burden (General Health Questionnaire-12), cost effectiveness (using Client Service Receipt Inventory) and institutionalization. These outcomes are assessed at baseline, 6, 18, 30 and 52 weeks. All participants will be subsequently followed for 3 years by telephone interview to record institutionalization.

Discussion: There is considerable debate about the clinical and cost effectiveness of anti-dementia drugs. DOMINO-AD seeks to provide clear evidence on the best treatment strategies for those managing patients at a particularly important clinical transition point.

Trial Registration: Current controlled trials ISRCTN49545035.
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July 2009

Cochrane column.

Int J Epidemiol 2006 Dec 12;35(6):1410-1. Epub 2006 Nov 12.

South African Cochrane Centre, Medical Research Council, PO Box 19070, Tygerberg 7505, South Africa.

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December 2006

Developing the BALANCE trail--the role of the pilot study and start-up phase.

Bipolar Disord 2004 Feb;6(1):26-31

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.

Objectives: The initial design of the BALANCE (Bipolar Affective disorder: Lithium / ANtiConvulsant Comparative Evaluation) Trial of maintenance treatment for bipolar disorder was based on the experience of previous trials in bipolar disorder and psychiatry and on the methods developed for large randomized trials in other areas of medicine. This report describes the adaptations to the initial design and trial procedures following the initial phases of the study. The rationale for the trial and full protocol have been published elsewhere.

Methods: A pilot study and start-up phase were used to check the tolerability of the interventions, refine the trial design and develop trial procedures that are acceptable to both clinicians and patients.

Results: Changes to the procedures included: the dropping of masking of allocated treatment from clinicians and participants; introduction of the use of postal delivery to supply medication; and dispensing with the proposed schedule of regular follow up appointments. In addition, support was made available to participating psychiatrists who often had limited experience of participating in randomized trials.

Conclusions: Pilot studies and start-up phases are essential to refine clinical trial design and allow development of procedures that are both methodologically rigorous and flexible and robust enough to promote recruitment and follow up. BALANCE is now actively recruiting in the UK and USA.
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February 2004

A 3-month, randomized, placebo-controlled, neuroleptic discontinuation study in 100 people with dementia: the neuropsychiatric inventory median cutoff is a predictor of clinical outcome.

J Clin Psychiatry 2004 Jan;65(1):114-9

Wolfson Research Centre, Newcastle General Hospital, Newcastle, UK.

Background: Although few placebo-controlled neuroleptic discontinuation studies have been conducted in people with dementia, such studies are essential to inform key clinical decisions.

Method: A 3-month, double-blind, placebo-controlled, neuroleptic discontinuation study (June 2000 to June 2002) was completed in 100 care-facility residents with probable or possible Alzheimer's disease (according to National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria) who had no severe behavioral disturbances and had been taking neuroleptics for longer than 3 months. The Neuropsychiatric Inventory (NPI) was used to measure changes in behavioral and psychiatric symptoms. Quality of life was evaluated using Dementia Care Mapping.

Results: Eighty-two patients completed the 1-month assessment (36 placebo, 46 active). The number of participants withdrawing overall (N = 14 [30%] placebo, N = 14 [26%] active treatment) and because of exacerbation of behavioral symptoms (N = 6 [13%] placebo, N = 5 [9%] active treatment) was similar in the neuroleptic- and placebo-treated patients. As hypothesized, patients with baseline NPI scores at or below the median (< or = 14) had a particularly good outcome, with a significantly greater reduction of agitation in the patients receiving placebo (Mann-Whitney U test, z = 2.4, p =.018), while patients with higher baseline NPI scores were significantly more likely to develop marked behavioral problems if discontinued from neuroleptics (chi(2) = 6.8, p =.009). There was no overall difference in the change of quality of life parameters between groups.

Discussion: A standardized evaluation with an instrument such as the NPI may be a clinical indicator of which people with dementia are likely to benefit from discontinuation of neuroleptic treatment.
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January 2004

Distant past exercise in women: measures may be reliable, but are they valid?

Med Sci Sports Exerc 2003 May;35(5):862-6

School of Health Care, Oxford Brookes University, Oxford, United Kingdom.

Introduction/purpose: Methods to measure lifetime physical activity have been described together with evidence suggesting that they are reliable. We present study findings that challenge the validity of such measures.

Methods: One hundred twenty-seven women aged 50-70 interviewed (31 cases, 96 controls) during a pilot case-control study about risk factors for osteoarthritis of the knee. Interviews used a life course approach with visual cues. Information obtained on past physical activity: (i) Total METs for a large range of activities within each decade between age 10 and age 50, (ii) 10-point rating scales representing level of physical activity during each decade between age 10 and age 50, and (iii) lifetime hours' participation in competitive sports.

Results: Any statistical correspondence between METs and activity rating scales was best in relation to women's activity when in their teens (Spearman rank correlation r = 0.40). The highest correlation thereafter related to the most recent decade (r = 0.25), which was low, but there was little or no linear association between MET values and the activity ratings when women were in their 20s or 30s. Around one fifth (20.4%) of women who reported no competitive sports participation during their teens and 18.5% who reported none during their 20s also reported total METs corresponding to the top quartile of physical activity during those periods of their lives.

Conclusion: Retrospective reports from women of distant past activity levels will likely yield different information depending on the form of questioning. It is unclear which method, if any, is accurate and unbiased. The validity of each method is therefore also questionable.
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May 2003

The prevalence of foot problems in older women: a cause for concern.

J Public Health Med 2002 Jun;24(2):77-84

OCHRAD, School of Health Care, Oxford Brookes University, Oxford.

Background: Painful feet are an extremely common problem amongst older women. Such problems increase the risk of falls and hamper mobility. The aetiology of painful and deformed feet is poorly understood.

Methods: Data were obtained during a pilot case-control study about past high heel usage in women, in relation to osteoarthritis of the knee. A total of 127 women aged 50-70 were interviewed (31 cases, 96 controls); case-control sets were matched for age. The following information was obtained about footwear: (1) age when first wore shoes with heels 1, 2 and 3 inches high; (2) height of heels worn for work; (3) maximum height of heels worn regularly for work, going out socially and for dancing, in 10-year age bands. Information about work-related activities and lifetime occupational history was gathered using a Life-Grid. The interview included a foot inspection.

Results: Foot problems, particularly foot arthritis, affected considerably more cases than controls (45 per cent versus 16 per cent, p = 0.001) and was considered a confounder. Cases were therefore excluded from subsequent analyses. Amongst controls, the prevalence of any foot problems was very high (83 per cent). All women had regularly worn one inch heels and few (8 per cent) had never worn 2 inch heels. Foot problems were significantly associated with a history of wearing relatively lower heels. Few work activities were related to foot problems; regular lifting was associated with foot pain (p = 0.03).

Conclusion: Most women in this age-group have been exposed to high-heeled shoes over many years, making aetiological research difficult in this area. Foot pain and deformities are widespread. The relationship between footwear, occupational activities and foot problems is a complex one that deserves considerably more research.
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June 2002

Evaluation of the Dartmouth COOP charts in a large-scale community survey in the United Kingdom.

J Public Health Med 2002 Jun;24(2):106-11

Health Services Research Unit, University of Oxford, Institute of Health Sciences, Headington.

Background: The aim of this study was to gain population norms for the COOP Charts in a large community sample, and to explore the construct validity, and whether the inclusion of the illustrations influences response rates.

Methods: A postal survey was carried out using a questionnaire booklet, containing the COOP Charts and a number of other items concerned with lifestyles and illness, sent to 6007 randomly selected subjects over the age of 18 years. Respondents were randomized to receiving the questionnaire booklet with a copy of the COOP Charts including illustrations, or the same booklet but including the COOP items without illustrations. The sample was drawn from the Family Health Services Authority (FHSA) computerized register for Oxfordshire. Outcome measures were scores for the eight dimensions of the COOP Charts.

Results: The survey achieved an adjusted response rate of 56.72 per cent. There was no difference in response rate or scores on the eight dimensions of the COOP Charts when broken down by those who received the illustrated Charts or simply the items from the measure without illustrations. Normative data for the COOP Charts are reported, broken down by age, sex, social class and whether respondent reported chronic illness or not.

Conclusion: The illustrations included in the original charts do not appear to influence response rates, or responses given to the questions. The evidence suggests that items of the COOP Charts provide a short and comprehensive survey of health status. The normative data provided in this paper may further facilitate their validation and use.
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June 2002