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2.  Draft Genome Comparison of Representatives of the Three Dominant Genotype Groups of Dairy Bacillus licheniformis Strains 
Applied and Environmental Microbiology  2014;80(11):3453-3462.
The spore-forming bacterium Bacillus licheniformis is a common contaminant of milk and milk products. Strains of this species isolated from dairy products can be differentiated into three major groups, namely, G, F1, and F2, using random amplification of polymorphic DNA (RAPD) analysis; however, little is known about the genomic differences between these groups and the identity of the fragments that make up their RAPD profiles. In this work we obtained high-quality draft genomes of representative strains from each of the three RAPD groups (designated strain G-1, strain F1-1, and strain F2-1) and compared them to each other and to B. licheniformis ATCC 14580 and Bacillus subtilis 168. Whole-genome comparison and multilocus sequence typing revealed that strain G-1 contains significant sequence variability and belongs to a lineage distinct from the group F strains. Strain G-1 was found to contain genes coding for a type I restriction modification system, urease production, and bacitracin synthesis, as well as the 8-kbp plasmid pFL7, and these genes were not present in strains F1-1 and F2-1. In agreement with this, all isolates of group G, but no group F isolates, were found to possess urease activity and antimicrobial activity against Micrococcus. Identification of RAPD band sequences revealed that differences in the RAPD profiles were due to differences in gene lengths, 3′ ends of predicted primer binding sites, or gene presence or absence. This work provides a greater understanding of the phylogenetic and phenotypic differences observed within the B. licheniformis species.
doi:10.1128/AEM.00065-14
PMCID: PMC4018868  PMID: 24657871
3.  Graphene surface plasmons at the near-infrared optical regime 
Scientific Reports  2014;4:6559.
Graphene has been identified as an emerging horizon for a nanoscale photonic platform because the Fermi level of intrinsic graphene can be engineered to support surface plasmons (SPs). The current solid back electrical gating and chemical doping methods cannot facilitate the demonstration of graphene SPs at the near-infrared (NIR) window because of the limited shift of the Fermi level. Here, we present the evidence for the existence of graphene SPs on a tapered graphene-silicon waveguide tip at a NIR wavelength, employing a surface carrier transfer method with molybdenum trioxides. The coupling between the graphene surface plasmons and the guiding mode in silicon waveguides allows for the observation of the concentrated field of the SPs in the tip by near-field scanning optical microscopy. Thus the hot spot from the concentrated SPs in the graphene layer can be used as a key experimental signature of graphene SPs. The NIR graphene SPs opens a new perspective for optical communications, optical sensing and imaging, and optical data storage with extreme spatial confinement, broad bandwidth and high tunability.
doi:10.1038/srep06559
PMCID: PMC4190570  PMID: 25297570
4.  Induction of labour in pre-eclamptic women: a randomised trial comparing the Foley balloon catheter with oral misoprostol 
Background
Between 40,000 and 80,000 pregnant women die annually from pre-eclampsia and eclampsia. Although magnesium sulphate and anti-hypertensive therapies can reduce the morbidity and mortality associated with pre-eclampsia, the only cure comes with delivery. Prompt delivery of the baby, preferably by vaginal route, is vital in order to achieve good maternal and neonatal outcomes. Induction of labour is therefore a critical intervention in order to prevent morbidity to both mother and baby. Two low cost interventions – oral misoprostol tablets and transcervical Foley catheterization – are already used by some in low resource settings, but their relative risks and benefits are not known. The trial will compare the risks, benefits, and trade-offs in efficacy, safety, acceptability and cost of misoprostol and Foley catheter for induction in women with preeclampsia or uncontrolled hypertension.
Methods/Design
A total of 602 women with an ongoing pregnancy with a live fetus requiring delivery because of pre-eclampsia or uncontrolled hypertension will be randomly assigned to labor induction with a transcervical Foley catheter or oral misoprostol 25 micrograms. Women will be recruited at two hospitals in Nagpur, India. The misoprostol group will receive oral misoprostol 25 microgram every 2 hours for a maximum of 12 doses or until active labor commences. The Foley group will undergo induction using a Foley catheter (silicone, size 18 F with 30 ml balloon) which will remain until active labor starts, the Foley catheter falls out, or 12 hours have elapsed. The primary outcome will be the attainment of vaginal delivery within 24 hours. Providers administering the treatment and those assessing the outcomes will not be blinded to group assignment.
Trial registration
NCT01801410 (ClinicalTrials.gov).
doi:10.1186/1471-2393-14-308
PMCID: PMC4261642  PMID: 25193157
Preeclampsia; Misoprostol; Foley catheter; Induction of labor
5.  Comparison of two alternative study designs in assessment of medicines utilisation in neonates 
Background
Estimates of prevalence are known to be affected by the design of cross-sectional studies. A pan-European study provided an opportunity to compare the effect of two cross-sectional study designs on estimates of medicines use.
Methods
A Service evaluation survey (SES) and a web-based point-prevalence study (PPS) were conducted as part of a European study of neonatal exposure to excipients. Neonatal units from all European Union countries plus Iceland, Norway, Switzerland and Serbia were invited to participate. All medicines prescribed to neonates were recorded during three-day and one-day study periods in the SES and PPS, respectively. In the PPS individual demographic and prescription data were also collected.
To compare the probabilities that a particular medicine would be reported by each study multilevel mixed effects logistic regression models with crossed random effects were applied. The relationship between medicines exposure at the unit and individual levels in the PPS data was assessed using polynomial regression with square root transformation.
Results
Of 31 invited countries 20 and 21 with 115 and 89 units joined the SES and PPS, respectively. Out of 5,572,859 live births in invited countries in 2010 a higher proportion was covered by units participating in the SES compared to the PPS (11% vs 6%, respectively; OR 1.89; 95% CI 1.87-1.89). A greater number of active pharmaceutical ingredients (API), manufacturers and trade names were registered in the SES compared to the PPS. High correlation between the two studies in frequency of use for each specified API was seen (R2 = 0.86). The average probability of a department to use a given API was greater in the SES compared to the PPS (OR 2.36; 95% CI 2.05-2.73) with higher frequency of use and longer average duration of prescription further increasing the difference. The polynomial regression model described the correlation between APIs exposure on unit and individual level well (R2 = 0.93).
Conclusion
The simple data structure and longer study period of the SES resulted in improved recruitment and higher likelihood of capture for a given API. The frequency of use at the unit level appears a good surrogate of individual exposure rates.
doi:10.1186/1471-2288-14-89
PMCID: PMC4110064  PMID: 25027048
Pharmacoepidemiologic methods; Cross-sectional studies; Data collection; Drug/excipient exposure
6.  Incidence, characteristics and risk factors of adverse drug reactions in hospitalized children – a prospective observational cohort study of 6,601 admissions 
BMC Medicine  2013;11:237.
Background
Adverse drug reactions (ADRs) are an important cause of harm in children. Current data are incomplete due to methodological differences between studies: only half of all studies provide drug data, incidence rates vary (0.6% to 16.8%) and very few studies provide data on causality, severity and risk factors of pediatric ADRs. We aimed to determine the incidence of ADRs in hospitalized children, to characterize these ADRs in terms of type, drug etiology, causality and severity and to identify risk factors.
Methods
We undertook a year-long, prospective observational cohort study of admissions to a single UK pediatric medical and surgical secondary and tertiary referral center (Alder Hey, Liverpool, UK). Children between 0 and 16 years 11 months old and admitted for more than 48 hours were included. Observed outcomes were occurrence of ADR and time to first ADR for the risk factor analysis.
Results
A total of 5,118 children (6,601 admissions) were included, 17.7% of whom experienced at least one ADR. Opiate analgesics and drugs used in general anesthesia (GA) accounted for more than 50% of all drugs implicated in ADRs. Of these ADRs, 0.9% caused permanent harm or required admission to a higher level of care. Children who underwent GA were at more than six times the risk of developing an ADR than children without a GA (hazard ratio (HR) 6.40; 95% confidence interval (CI) 5.30 to 7.70). Other factors increasing the risk of an ADR were increasing age (HR 1.06 for each year; 95% CI 1.04 to 1.07), increasing number of drugs (HR 1.25 for each additional drug; 95% CI 1.22 to 1.28) and oncological treatment (HR 1.90; 95% CI 1.40 to 2.60).
Conclusions
ADRs are common in hospitalized children and children who had undergone a GA had more than six times the risk of developing an ADR. GA agents and opiate analgesics are a significant cause of ADRs and have been underrepresented in previous studies. This is a concern in view of the increasing number of pediatric short-stay surgeries.
doi:10.1186/1741-7015-11-237
PMCID: PMC4225679  PMID: 24228998
Adverse drug reactions; Drug safety; Hospitalized children; Risk factors; General anesthesia; Peri- and post-operative pain management
7.  Adverse drug reactions and off-label and unlicensed medicines in children: a nested case?control study of inpatients in a pediatric hospital 
BMC Medicine  2013;11:238.
Background
Off-label and unlicensed (OLUL) prescribing has been prevalent in pediatric practice. Using data from a prospective cohort study of adverse drug reactions (ADRs) among pediatric inpatients, we aimed to test the hypothesis that OLUL status is a risk factor for ADRs.
Methods
A nested case?control study was conducted within a prospective cohort study. Details of all medicines administered were recorded, including information about OLUL status. The odds ratio for OLUL medicines being implicated in a probable or definite ADR was calculated. A multivariate Cox proportional hazards regression model was fitted to the data to assess the influence that OLUL medicine use had on the hazard of an ADR occurring.
Results
A total of 10,699 medicine courses were administered to 1,388 patients. The odds ratio (OR) of an OLUL medicine being implicated in an ADR compared with an authorized medicine was 2.25 (95% confidence interval (CI) 1.95 to 2.59). Medicines licensed in children but given to a child below the minimum age or weight had the greatest odds of being implicated in an ADR (19% of courses in this category were implicated, OR 3.54 (95% CI 2.82 to 4.44). Each additional OLUL medicine given significantly increased the hazard of an ADR (hazard ratio (HR) 1.3 95% CI 1.2 to 1.3, P <0.001). Each additional authorized medicine given also significantly increased the hazard (HR 1.2 95% CI 1.2 to 1.3, P <0.001).
Conclusions
OLUL medicines are more likely to be implicated in an ADR than authorized medicines. The number of medicines administered is a risk factor for ADRs highlighting the need to use the lowest number of medicines, at the lowest dose for the shortest period, with continual vigilance by prescribers, in order to reduce the risk of ADRs.
doi:10.1186/1741-7015-11-238
PMCID: PMC4231613  PMID: 24229060
Adverse drug reactions; Pediatrics; Prescribing; Off-label; Unlicensed
8.  An explanatory randomised placebo controlled trial of levothyroxine supplementation for babies born <28 weeks’ gestation: results of the TIPIT trial 
Trials  2013;14:211.
Background
Babies born before 28 weeks’ gestation have lower plasma thyroid hormone concentrations than more mature infants. This may contribute to their risk of poor developmental outcome. Previous studies have suggested that thyroxine supplementation for extremely preterm neonates may be beneficial. The aim of this study was to investigate the effect of administration of supplemental thyroxine to very premature babies on brain size and somatic growth at 36 weeks’ corrected gestational age (CGA).
Methods
In this explanatory multicentre double blind randomised placebo controlled trial, 153 infants born below 28 weeks’ gestation were randomised to levothyroxine (LT4) supplementation or placebo until 32 weeks’ CGA. The primary outcome was brain size assessed by the width of the subarachnoid space measured by cranial ultrasound at 36 weeks’ CGA. Lower leg length was measured by knemometry.
Results
Babies in the LT4-supplemented and placebo groups had similar baseline characteristics. There were no significant differences between infants given LT4 (n=78) or placebo (n=75) for width of the subarachnoid space, head circumference at 36 weeks’ CGA, body weight at 36 weeks’ CGA or mortality. Infants who received LT4 had significantly shorter leg lengths at 36 weeks’ CGA although adjusted analysis for baseline length did not find a statistical difference. There was a significant correlation between low FT4 and wider subarachnoid space. No unexpected serious adverse events were noted and incidence of adverse events did not differ between the two groups.
Conclusion
This is the only randomised controlled trial of thyroxine supplementation targeting extremely premature infants. Supplementing all babies below 28 weeks’ gestation with LT4 had no apparent effect on brain size. These results do not support routine supplementation with LT4 for all babies born below 28 weeks’ gestation.
Trial registration
Current Controlled Trials ISRCTN89493983
EUDRACT number: 2005-003-09939
doi:10.1186/1745-6215-14-211
PMCID: PMC3711854  PMID: 23841945
Thyroxine supplementation; RCT; Extreme preterm; Brain; Growth
9.  Influenza Risk Management: Lessons Learned from an A(H1N1) pdm09 Outbreak Investigation in an Operational Military Setting 
PLoS ONE  2013;8(7):e68639.
Background
At the onset of an influenza pandemic, when the severity of a novel strain is still undetermined and there is a threat of introduction into a new environment, e.g., via the deployment of military troops, sensitive screening criteria and conservative isolation practices are generally recommended.
Objectives
In response to elevated rates of influenza-like illness among U.S. military base camps in Kuwait, U.S. Naval Medical Research Unit No. 3 partnered with local U.S. Army medical units to conduct an A(H1N1) pdm09 outbreak investigation.
Patients/Methods
Initial clinical data and nasal specimens were collected via the existent passive surveillance system and active surveillance was conducted using a modified version of the World Health Organization/U.S. Centers for Disease Control and Prevention influenza-like illness case definition [fever (T > 100.5˚F/38˚C) in addition to cough and/or sore throat in the previous 72 hours] as the screening criteria. Samples were tested via real-time reverse-transcription PCR and sequenced for comparison to global A(H1N1) pdm09 viruses from the same time period.
Results
The screening criteria used in Kuwait proved insensitive, capturing only 16% of A(H1N1) pdm09-positive individuals. While still not ideal, using cough as the sole screening criteria would have increased sensitivity to 73%.
Conclusions
The results of and lessons learned from this outbreak investigation suggest that pandemic influenza risk management should be a dynamic process (as information becomes available regarding true attack rates and associated mortality, screening and isolation criteria should be re-evaluated and revised as appropriate), and that military operational environments present unique challenges to influenza surveillance.
doi:10.1371/journal.pone.0068639
PMCID: PMC3707881  PMID: 23874699
10.  The effect of carbohydrate and marine peptide hydrolysate co-ingestion on endurance exercise metabolism and performance 
Background
The purpose of this study was to examine the efficacy of introducing a fish protein hydrolysate (PEP) concurrently with carbohydrate (CHO) and whey protein (PRO) on endurance exercise metabolism and performance.
Methods
In a randomised, double blind crossover design, 12 male volunteers completed an initial familiarisation followed by three experimental trials. The trials consisted of a 90 min cycle task corresponding to 50% of predetermined maximum power output, followed by a 5 km time trial (TT). At 15 min intervals during the 90 min cycle task, participants consumed 180 ml of CHO (67 g.hr-1 of maltodextrin), CHO-PRO (53.1 g.hr of CHO, 13.6 g.hr-1 of whey protein) or CHO-PRO-PEP (53.1 g.hr-1 of CHO, 11 g.hr-1 of whey protein and 2.4 g.hr-1of hydrolyzed marine peptides).
Results and conclusions
During the 90 min cycle task, the respiratory exchange ratio (RER) in the CHO-PRO condition was significantly higher than CHO (p < 0.001) and CHO-PRO-PEP (p < 0.001). Additionally, mean heart rate for the CHO condition was significantly lower than that for CHO-PRO (p = 0.021). Time-to-complete the 5 km TT was not significantly different between conditions (m ± SD: 456 ± 16, 456 ± 18 and 455 ± 21 sec for CHO, CHO-PRO and CHO-PRO-PEP respectively, p = 0.98). Although the addition of hydrolyzed marine peptides appeared to influence metabolism during endurance exercise in the current study, it did not provide an ergogenic benefit as assessed by 5 km TT performance.
doi:10.1186/1550-2783-10-29
PMCID: PMC3674971  PMID: 23724789
Marine peptide; Hydrolyzed protein; Exercise metabolism
11.  Manipulation of drugs to achieve the required dose is intrinsic to paediatric practice but is not supported by guidelines or evidence 
BMC Pediatrics  2013;13:81.
Background
A lack of age-appropriate formulations can make it difficult to administer medicines to children. A manipulation of the dosage form may be required to achieve the required dose. This study aimed to describe medicines that are manipulated to achieve the required dose in paediatric practice.
Method
A structured, undisguised observational study and postal survey. The observational study investigated drug manipulations occurring in clinical practice across three sites. The questionnaire, administered to a sample of paediatric nurses throughout the UK, surveyed manipulations conducted and nurses’ experiences and views.
Results
The observational study identified 310 manipulations, of which 62% involved tablets, 21% were intravenous drugs and 10% were sachets. Of the 54 observed manipulations 40 involved tablets with 65% of the tablets being cut and 30% dispersed to obtain a smaller dose. 188 manipulations were reported by questionnaire respondents, of these 46% involved tablets, 12% were intravenous drugs, and 12% were nebuliser solutions. Manipulations were predominantly, but not exclusively, identified in specialist clinical areas with more highly dependent patients. Questionnaire respondents were concerned about the accuracy of the dose achieved following manipulations and the lack of practice guidance.
Conclusion
Manipulations to achieve the required dose occur throughout paediatric in-patient settings. The impact of manipulations on the efficacy of the drugs, the accuracy of the dose and any adverse effects on patients is not known. There is a need to develop evidence-based guidance for manipulations of medicines in children.
doi:10.1186/1471-2431-13-81
PMCID: PMC3691579  PMID: 23688279
Drug manipulation; Survey; Dosage forms; Children's medicines
12.  Heat Resistance and Salt Hypersensitivity in Lactococcus lactis Due to Spontaneous Mutation of llmg_1816 (gdpP) Induced by High-Temperature Growth 
Applied and Environmental Microbiology  2012;78(21):7753-7759.
During construction of several gene deletion mutants in Lactococcus lactis MG1363 which involved a high-temperature (37.5°C) incubation step, additional spontaneous mutations were observed which resulted in stable heat resistance and in some cases salt-hypersensitive phenotypes. Whole-genome sequencing of one strain which was both heat resistant and salt hypersensitive, followed by PCR and sequencing of four other mutants which shared these phenotypes, revealed independent mutations in llmg_1816 in all cases. This gene encodes a membrane-bound stress signaling protein of the GdpP family, members of which exhibit cyclic dimeric AMP (c-di-AMP)-specific phosphodiesterase activity. Mutations were predicted to lead to single amino acid substitutions or protein truncations. An independent llmg_1816 mutant (Δ1816), created using a suicide vector, also displayed heat resistance and salt hypersensitivity phenotypes which could be restored to wild-type levels following plasmid excision. L. lactis Δ1816 also displayed improved growth in response to sublethal concentrations of penicillin G. High-temperature incubation of a wild-type industrial L. lactis strain also resulted in spontaneous mutation of llmg_1816 and heat-resistant and salt-hypersensitive phenotypes, suggesting that this is not a strain-specific phenomenon and that it is independent of a plasmid integration event. Acidification of milk by the llmg_1816-altered strain was inhibited by lower salt concentrations than the parent strain. This study demonstrates that spontaneous mutations can occur during high-temperature growth of L. lactis and that inactivation of llmg_1816 leads to temperature resistance and salt hypersensitivity.
doi:10.1128/AEM.02316-12
PMCID: PMC3485701  PMID: 22923415
13.  Genotyping of Present-Day and Historical Geobacillus Species Isolates from Milk Powders by High-Resolution Melt Analysis of Multiple Variable-Number Tandem-Repeat Loci 
Applied and Environmental Microbiology  2012;78(19):7090-7097.
Spores of thermophilic Geobacillus species are a common contaminant of milk powder worldwide due to their ability to form biofilms within processing plants. Genotyping methods can provide information regarding the source and monitoring of contamination. A new genotyping method was developed based on multilocus variable-number tandem-repeat (VNTR) analysis (MLVA) in conjunction with high-resolution melt analysis (MLV-HRMA) and compared to the currently used method, randomized amplified polymorphic DNA PCR (RAPD-PCR). Four VNTR loci were identified and used to genotype 46 Geobacillus isolates obtained from retailed powder and samples from 2 different milk powder processing plants. These 46 isolates were differentiated into 16 different groups using MLV-HRMA (D = 0.89). In contrast, only 13 RAPD-PCR genotypes were identified among the 46 isolates (D = 0.79). This new method was then used to analyze 35 isolates obtained from powders with high spore counts (>104 spores · g−1) from a single processing plant together with 27 historical isolates obtained from powder samples processed in the same region of Australia 17 years ago. Results showed that three genotypes can coexist in a single processing run, while the same genotypes observed 17 years ago are present today. While certain genotypes could be responsible for powders with high spore counts, there was no correlation to specific genotypes being present in powder plants and retailed samples. In conclusion, the MLV-HRMA method is useful for genotyping Geobacillus spp. to provide insight into the prevalence and persistence of certain genotypes within milk powder processing plants.
doi:10.1128/AEM.01817-12
PMCID: PMC3457474  PMID: 22865061
14.  Adverse Drug Reactions Causing Admission to a Paediatric Hospital 
PLoS ONE  2012;7(12):e50127.
Objective(s)
To obtain reliable information about the incidence of adverse drug reactions, and identify potential areas where intervention may reduce the burden of ill-health.
Design
Prospective observational study.
Setting
A large tertiary children’s hospital providing general and specialty care in the UK.
Participants
All acute paediatric admissions over a one year period.
Main Exposure
Any medication taken in the two weeks prior to admission.
Outcome Measures
Occurrence of adverse drug reaction.
Results
240/8345 admissions in 178/6821 patients admitted acutely to a paediatric hospital were thought to be related to an adverse drug reaction, giving an estimated incidence of 2.9% (95% CI 2.5, 3.3), with the reaction directly causing, or contributing to the cause, of admission in 97.1% of cases. No deaths were attributable to an adverse drug reaction. 22.1% (95% CI 17%, 28%) of the reactions were either definitely or possibly avoidable. Prescriptions originating in the community accounted for 44/249 (17.7%) of adverse drug reactions, the remainder originating from hospital. 120/249 (48.2%) reactions resulted from treatment for malignancies. The drugs most commonly implicated in causing admissions were cytotoxic agents, corticosteroids, non-steroidal anti-inflammatory drugs, vaccines and immunosuppressants. The most common reactions were neutropenia, immunosuppression and thrombocytopenia.
Conclusions
Adverse drug reactions in children are an important public health problem. Most of those serious enough to require hospital admission are due to hospital-based prescribing, of which just over a fifth may be avoidable. Strategies to reduce the burden of ill-health from adverse drug reactions causing admission are needed.
doi:10.1371/journal.pone.0050127
PMCID: PMC3514275  PMID: 23226510
15.  Enhancing Communication about Paediatric Medicines: Lessons from a Qualitative Study of Parents' Experiences of Their Child's Suspected Adverse Drug Reaction 
PLoS ONE  2012;7(10):e46022.
Background
There is little research on parents' experiences of suspected adverse drug reactions in their children and hence little evidence to guide clinicians when communicating with families about problems associated with medicines.
Objective
To identify any unmet information and communication needs described by parents whose child had a suspected adverse drug reaction.
Methods
Semi-structured qualitative interviews with parents of 44 children who had a suspected adverse drug reaction identified on hospital admission, during in-patient treatment or reported by parents using the Yellow Card Scheme (the UK system for collecting spontaneous reports of adverse drug reactions). Interviews were conducted face-to-face or by telephone; most interviews were audiorecorded and transcribed. Analysis was informed by the principles of the constant comparative method.
Results
Many parents described being dissatisfied with how clinicians communicated about adverse drug reactions and unclear about the implications for their child's future use of medicines. A few parents felt that clinicians had abandoned their child and reported refusing the use of further medicines because they feared a repeated adverse drug reaction. The accounts of parents of children with cancer were different. They emphasised their confidence in clinicians' management of adverse drug reactions and described how clinicians prospectively explained the risks associated with medicines. Parents linked symptoms to medicines in ways that resembled the established reasoning that clinicians use to evaluate the possibility that a medicine has caused an adverse drug reaction.
Conclusion
Clinicians' communication about adverse drug reactions was poor from the perspective of parents, indicating that improvements are needed. The accounts of parents of children with cancer indicate that prospective explanation about adverse drug reactions at the time of prescription can be effective. Convergence between parents and clinicians in their reasoning for linking children's symptoms to medicines could be a starting point for improved communication.
doi:10.1371/journal.pone.0046022
PMCID: PMC3468607  PMID: 23071535
16.  Wide intra- and inter-country variability in drug use and dosage in very-low-birth-weight newborns with severe infections 
Purpose
To describe the use of ciprofloxacin and fluconazole for the treatment of sepsis in European neonatal intensive care units (NICUs) in order to better orient research aimed at acquiring essential knowledge in this critical area.
Methods
The survey consisted of an online questionnaire for all participating NICUs on treatment schemes employed, rationales behind drug choices and interest in participation in research involving the two drugs.
Results
A total of 189 level II and III NICUs participated in the survey, representing 25 countries, with Italy, UK and France providing the greatest number of centres (54 % of total). Ciprofloxacin is used in 25 % of NICUs that responded, although the indications for administering it vary between centres and the dosage ranges vary considerably, with 25 % of NICUs giving ≤10 mg/kg/day and another 25 % giving ≥21 mg/kg/day. Factors given as affecting the decision to use ciprofloxacin are uncertainty about its safety and pharmacokinetics and level of penetration in the cerebrospinal fluid. Among the 70 % of responding units that use fluconazole to treat fungal infection, 45 % administer 6 mg/kg unit doses while 33 % administer 12 mg/kg; 41 % of NICUs use a 24-h interval between administrations while 20 % wait 72 h. Among the responding NICUs, 57 % were willing to participate in a project on ciprofloxacin and 59 % would consider participating in a randomized controlled trial evaluating fluconazole versus micafungin.
Conclusions
Great variability in therapies exists within and between countries. Numerous centres are interested in participating in research on these drugs, highlighting the need for further knowledge on sepsis treatment and European centres’ interest in off-patent medicine research.
doi:10.1007/s00228-012-1415-2
PMCID: PMC3621995  PMID: 23052414
Data collection; Intensive care units, neonatal; Sepsis; Ciprofloxacin; Fluconazole
17.  Hospitalised neonates in Estonia commonly receive potentially harmful excipients 
BMC Pediatrics  2012;12:136.
Background
Information on the neonatal exposure to excipients is limited. Our aim was to describe the extent of excipient intake by Estonian neonates; to classify the excipients according to potential neonatal toxicity and thereby to measure the extent of exposure of neonates to potentially harmful excipients.
Methods
A prospective cohort study that recorded all medicines prescribed to patients aged below 28 days admitted to Tartu University Hospital from 01.02-01.08 2008 and to Tallinn Children’s Hospital from 01.02- 01.08 2009 was conducted. Excipients were identified from Summaries of Product Characteristics and classified according to toxicity following a literature review.
Results
1961 prescriptions comprising 107 medicines were written for 348/490 neonates admitted. A total of 123 excipients were found in 1620 (83%) prescriptions and 93 (87%) medicines. 47 (38%) of these excipients were classified as potentially or known to be harmful to neonates. Most neonates (97%) received at least one medicine (median number 2) with potentially or known to be harmful excipient. Parabens were the most commonly used known to be harmful excipients and sodium metabisulphite the most commonly used potentially harmful excipient, received by 343 (99%) and 297 (85%) of treated neonates, respectively.
Conclusions
Hospitalised neonates in Estonia are commonly receiving a wide range of excipients with their medication. Quantitative information about excipients should be made available to pharmacists and neonatologists helping them to take into account excipient issues when selecting medicines and to monitor for adverse effects if administration of medicines containing excipients is unavoidable.
doi:10.1186/1471-2431-12-136
PMCID: PMC3483231  PMID: 22931304
Harmful excipient; Neonate
18.  Mechanism-Based Urinary Biomarkers to Identify the Potential for Aminoglycoside-Induced Nephrotoxicity in Premature Neonates: A Proof-of-Concept Study 
PLoS ONE  2012;7(8):e43809.
Premature infants are frequently exposed to aminoglycoside antibiotics. Novel urinary biomarkers may provide a non-invasive means for the early identification of aminoglycoside-related proximal tubule renal toxicity, to enable adjustment of treatment and identification of infants at risk of long-term renal impairment. In this proof-of-concept study, urine samples were collected from 41 premature neonates (≤32 weeks gestation) at least once per week, and daily during courses of gentamicin, and for 3 days afterwards. Significant increases were observed in the three urinary biomarkers measured (Kidney Injury Molecule-1 (KIM-1), Neutrophil Gelatinase-associated Lipocalin (NGAL), and N-acetyl-β-D-glucosaminidase (NAG)) during treatment with multiple courses of gentamicin. When adjusted for potential confounders, the treatment effect of gentamicin remained significant only for KIM-1 (mean difference from not treated, 1.35 ng/mg urinary creatinine; 95% CI 0.05–2.65). Our study shows that (a) it is possible to collect serial urine samples from premature neonates, and that (b) proximal tubule specific urinary biomarkers can act as indicators of aminoglycoside-associated nephrotoxicity in this age group. Further studies to investigate the clinical utility of novel urinary biomarkers in comparison to serum creatinine need to be undertaken.
doi:10.1371/journal.pone.0043809
PMCID: PMC3427159  PMID: 22937100
19.  Development and Inter-Rater Reliability of the Liverpool Adverse Drug Reaction Causality Assessment Tool 
PLoS ONE  2011;6(12):e28096.
Aim
To develop and test a new adverse drug reaction (ADR) causality assessment tool (CAT).
Methods
A comparison between seven assessors of a new CAT, formulated by an expert focus group, compared with the Naranjo CAT in 80 cases from a prospective observational study and 37 published ADR case reports (819 causality assessments in total).
Main Outcome Measures
Utilisation of causality categories, measure of disagreements, inter-rater reliability (IRR).
Results
The Liverpool ADR CAT, using 40 cases from an observational study, showed causality categories of 1 unlikely, 62 possible, 92 probable and 125 definite (1, 62, 92, 125) and ‘moderate’ IRR (kappa 0.48), compared to Naranjo (0, 100, 172, 8) with ‘moderate’ IRR (kappa 0.45). In a further 40 cases, the Liverpool tool (0, 66, 81, 133) showed ‘good’ IRR (kappa 0.6) while Naranjo (1, 90, 185, 4) remained ‘moderate’.
Conclusion
The Liverpool tool assigns the full range of causality categories and shows good IRR. Further assessment by different investigators in different settings is needed to fully assess the utility of this tool.
doi:10.1371/journal.pone.0028096
PMCID: PMC3237416  PMID: 22194808
20.  Risk profile and outcomes of aortic valve replacement in octogenarians 
World Journal of Cardiology  2011;3(11):359-366.
AIM: To investigate the patient characteristics, relationship between the Logistic EuroSCORE (LES) and the observed outcomes in octogenarians who underwent surgical aortic valve replacement (AVR).
METHODS: Two hundred and seventy three octogenarians underwent AVR between 1996 and 2008 at Bristol Royal Infirmary. Demographics, acute outcomes, length of hospital stay and mortality were obtained. The LES was calculated to characterize the predicted operative risk. Two groups were defined: LES ≥ 15 (n = 80) and LES < 15 (n = 193).
RESULTS: In patients with LES ≥ 15, 30 d mortality was 14% (95% CI: 7%-23%) compared with 4% (95% CI: 2%-8%) in the LES < 15 group (P < 0.007). Despite the increase in number of operations from 1996 to 2008, the average LES did not change. Only 5% of patients had prior bypass surgery. The LES identified a low risk quartile of patients with a very low mortality (4%, n = 8, P < 0.007) at 30 d. The overall surgical results for octogenarians were excellent. The low risk group had an excellent outcome and the high risk group had a poor outcome after surgical AVR.
CONCLUSION: It may be better treated with transcatheter aortic valve implantation.
doi:10.4330/wjc.v3.i11.359
PMCID: PMC3224869  PMID: 22125671
Aortic valve replacement; Transcatheter aortic valve implantation; Logistic EuroSCORE; Coronary artery bypass grafting
21.  Tumour necrosis factor receptor trafficking dysfunction opens the TRAPS door to pro-inflammatory cytokine secretion 
Bioscience Reports  2011;32(Pt 2):105-112.
Cytokines are secreted from macrophages and other cells of the immune system in response to pathogens. Additionally, in autoinflammatory diseases cytokine secretion occurs in the absence of pathogenic stimuli. In the case of TRAPS [TNFR (tumour necrosis factor receptor)-associated periodic syndrome], inflammatory episodes result from mutations in the TNFRSF1A gene that encodes TNFR1. This work remains controversial, however, with at least three distinct separate mechanisms of receptor dysfunction having been proposed. Central to these hypotheses are the NF-κB (nuclear factor κB) and MAPK (mitogen-activated protein kinase) families of transcriptional activators that are able to up-regulate expression of a number of genes, including pro-inflammatory cytokines. The present review examines each proposed mechanism of TNFR1 dysfunction, and addresses how these processes might ultimately impact upon cytokine secretion and disease pathophysiology.
doi:10.1042/BSR20110089
PMCID: PMC3204872  PMID: 22115362
mitogen-activated protein kinase (MAPK); nuclear factor κB (NF-κB); periodic syndrome; tumour necrosis factor (TNF); tumour necrosis factor receptor-associated periodic syndrome (TRAPS); ADAM, a disintegrin and metalloproteinase; AP, activator protein; APR, acute phase response; ATF6, activating transcription factor 6; CRD, cysteine-rich domain; CREBH, cAMP-responsive-element-binding protein H; CRP, C-reactive protein; ER, endoplasmic reticulum; IFN, interferon; IRF, IFN-regulatory factor; JNK, c-Jun N-terminal kinase; IL, interleukin; JAK/STAT, Janus kinase/signal transducer and activator of transcription; mAb, monoclonal antibody; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor κB; PBMC, peripheral blood mononuclear cell; ROS, reactive oxygen species; SAP, serum amyloid P; TNF, tumour necrosis factor; TACE, TNFα-converting enzyme; TNFR, TNF receptor; sTNFR1, soluble TNFR1; TRAPS, TNFR-associated periodic syndrome; UPR, unfolded protein response
22.  The effects of Energised Greens™ upon blood acid-base balance during resting conditions 
Background
The consumption of fresh fruit & vegetable in concentrate form (FVC) have recently become an alternative approach to combating excessive renal acid loads often associated with Western Diets. Additionally, these FVC's have been purported to induce metabolic alkalosis, which perhaps may enhance the blood buffering capacity of an individual. Therefore, the aim of this preliminary study was to profile the acid-base response after ingestion of an acute dose of fruit and vegetable extract (Energised Greens™ (EG), Nottingham, UK) and compare it to a standard, low dose (0.1 g·kg-1) of sodium bicarbonate (NaHCO3).
Findings
As part of a randomized, cross over design participants consumed 750 mL of water with either 9 g of EG (manufacturer recommendations), 0.1 g·kg-1 of NaHCO3 or a placebo (plain flour) in opaque encapsulated pills following an overnight fast. Capillary samples were obtained and analyzed every 15 min for a period of 120 min following ingestion. Significant interactions (p < 0.01), main effects for condition (p < 0.001) and time (p < 0.001) were evident for all acid-base variables (pH, HCO3-, BE). Interactions indicated significant elevation in blood alkalosis for only the NaHCO3 condition when compared to both placebo and EG from 15 to 120 minutes.
Conclusions
Despite previous findings of elevated blood pH following acute mineral supplementation, manufacturer recommended doses of EG do not induce any significant changes in acid-base regulation in resting males.
doi:10.1186/1550-2783-8-14
PMCID: PMC3215167  PMID: 21992467
23.  SCAMP: standardised, concentrated, additional macronutrients, parenteral nutrition in very preterm infants: a phase IV randomised, controlled exploratory study of macronutrient intake, growth and other aspects of neonatal care 
BMC Pediatrics  2011;11:53.
Background
Infants born <29 weeks gestation are at high risk of neurocognitive disability. Early postnatal growth failure, particularly head growth, is an important and potentially reversible risk factor for impaired neurodevelopmental outcome. Inadequate nutrition is a major factor in this postnatal growth failure, optimal protein and calorie (macronutrient) intakes are rarely achieved, especially in the first week. Infants <29 weeks are dependent on parenteral nutrition for the bulk of their nutrient needs for the first 2-3 weeks of life to allow gut adaptation to milk digestion. The prescription, formulation and administration of neonatal parenteral nutrition is critical to achieving optimal protein and calorie intake but has received little scientific evaluation. Current neonatal parenteral nutrition regimens often rely on individualised prescription to manage the labile, unpredictable biochemical and metabolic control characteristic of the early neonatal period. Individualised prescription frequently fails to translate into optimal macronutrient delivery. We have previously shown that a standardised, concentrated neonatal parenteral nutrition regimen can optimise macronutrient intake.
Methods
We propose a single centre, randomised controlled exploratory trial of two standardised, concentrated neonatal parenteral nutrition regimens comparing a standard macronutrient content (maximum protein 2.8 g/kg/day; lipid 2.8 g/kg/day, dextrose 10%) with a higher macronutrient content (maximum protein 3.8 g/kg/day; lipid 3.8 g/kg/day, dextrose 12%) over the first 28 days of life. 150 infants 24-28 completed weeks gestation and birthweight <1200 g will be recruited. The primary outcome will be head growth velocity in the first 28 days of life. Secondary outcomes will include a) auxological data between birth and 36 weeks corrected gestational age b) actual macronutrient intake in first 28 days c) biomarkers of biochemical and metabolic tolerance d) infection biomarkers and other intravascular line complications e) incidence of major complications of prematurity including mortality f) neurodevelopmental outcome at 2 years corrected gestational age
Trial registration
Current controlled trials: ISRCTN76597892; EudraCT Number: 2008-008899-14
doi:10.1186/1471-2431-11-53
PMCID: PMC3141505  PMID: 21663622
24.  Infant skin-cleansing product versus water: A pilot randomized, assessor-blinded controlled trial 
BMC Pediatrics  2011;11:35.
Background
The vulnerability of newborn babies' skin creates the potential for a number of skin problems. Despite this, there remains a dearth of good quality evidence to inform practice. Published studies comparing water with a skin-cleansing product have not provided adequate data to inform an adequately powered trial. Nor have they distinguished between babies with and without a predisposition to atopic eczema. We conducted a pilot study as a prequel to designing an optimum trial to investigate whether bathing with a specific cleansing product is superior to bathing with water alone. The aims were to produce baseline data which would inform decisions for the main trial design (i.e. population, primary outcome, sample size calculation) and to optimize the robustness of trial processes within the study setting.
Methods
100 healthy, full term neonates aged <24 hours were randomly assigned to bathing with water and cotton wool (W) or with a cleaning product (CP). A minimum of bathing 3 times per week was advocated. Groups were stratified according to family history of atopic eczema. Transepidermal water loss (TEWL), stratum corneum hydration and skin surface pH were measured within 24 hours of birth and at 4 and 8 weeks post birth. Measurements were taken on the thigh, forearm and abdomen. Women also completed questionnaires and diaries to record bathing practices and medical treatments.
Results
Forty nine babies were randomized to cleansing product, 51 to water. The 95% confidence intervals (CI) for the average TEWL measurement at each time point were: whole sample at baseline: 10.8 g/m2/h to 11.7 g/m2/h; CP group 4 weeks: 10.9 g/m2/h to 13.3 g/m2/h; 8 weeks: 11.4 g/m2/h to 12.9 g/m2/h; W group 4 weeks:10.9 g/m2/h to 12.2 g/m2/h; 8 weeks: 11.4 g/m2/h to 12.9 g/m2/h.
Conclusion
This pilot study provided valuable baseline data and important information on trial processes. The decision to proceed with a superiority trial, for example, was inconsistent with our data; therefore a non-inferiority trial is recommended.
Trial registration
ISRCTN72285670
doi:10.1186/1471-2431-11-35
PMCID: PMC3112109  PMID: 21569487
25.  Class II Phosphoinositide 3-Kinase Regulates Exocytosis of Insulin Granules in Pancreatic β Cells* 
The Journal of Biological Chemistry  2010;286(6):4216-4225.
Phosphoinositide 3-kinases (PI3Ks) are critical regulators of pancreatic β cell mass and survival, whereas their involvement in insulin secretion is more controversial. Furthermore, of the different PI3Ks, the class II isoforms were detected in β cells, although their role is still not well understood. Here we show that down-regulation of the class II PI3K isoform PI3K-C2α specifically impairs insulin granule exocytosis in rat insulinoma cells without affecting insulin content, the number of insulin granules at the plasma membrane, or the expression levels of key proteins involved in insulin secretion. Proteolysis of synaptosomal-associated protein of 25 kDa, a process involved in insulin granule exocytosis, is impaired in cells lacking PI3K-C2α. Finally, our data suggest that the mRNA for PI3K-C2α may be down-regulated in islets of Langerhans from type 2 diabetic compared with non-diabetic individuals. Our results reveal a critical role for PI3K-C2α in β cells and suggest that down-regulation of PI3K-C2α may be a feature of type 2 diabetes.
doi:10.1074/jbc.M110.200295
PMCID: PMC3039383  PMID: 21127054
Diabetes; Exocytosis; Insulin Secretion; Phosphatidylinositol 3-Kinase; Signal Transduction

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