bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural Similarities and Differences between Two Functionally Distinct SecA Proteins, Mycobacterium tuberculosis SecA1 and SecA2
Authors: Swanson Stephanie , Ioerger Thomas R. , Rigel Nathan W. , Miller Brittany K. , Braunstein Miriam , Sacchettini James C. 
Published: December 2015

ABSTRACT

While SecA is the ATPase component of the major bacterial secretory (Sec) system, mycobacteria and some Gram-positive pathogens have a second paralog, SecA2. In bacteria with two SecA paralogs, each SecA is functionally distinct, and they cannot compensate for one another. Compared to SecA1, SecA2 exports a distinct and smaller set of substrates, some of which have roles in virulence. In the mycobacterial system, some SecA2-dependent substrates lack a signal peptide, while others contain a signal peptide but possess features in the mature protein that necessitate a role for SecA2 in their export. It is unclear how SecA2 functions in protein export, and one open question is whether SecA2 works with the canonical SecYEG channel to export proteins. In this study, we report the structure of
Mycobacterium tuberculosis
SecA2 (
Mtb
SecA2), which is the first structure of any SecA2 protein. A high level of structural similarity is observed between SecA2 and SecA1. The major structural difference is the absence of the helical wing domain, which is likely to play a role in how
Mtb
SecA2 recognizes its unique substrates. Importantly, structural features critical to the interaction between SecA1 and SecYEG are preserved in SecA2. Furthermore, suppressor mutations of a dominant-negative
secA2
mutant map to the surface of SecA2 and help identify functional regions of SecA2 that may promote interactions with SecYEG or the translocating polypeptide substrate. These results support a model in which the mycobacterial SecA2 works with SecYEG.

IMPORTANCE
SecA2 is a paralog of SecA1, which is the ATPase of the canonical bacterial Sec secretion system. SecA2 has a nonredundant function with SecA1, and SecA2 exports a distinct and smaller set of substrates than SecA1. This work reports the crystal structure of SecA2 of
Mycobacterium tuberculosis
(the first SecA2 structure reported for any organism). Many of the structural features of SecA1 are conserved in the SecA2 structure, including putative contacts with the SecYEG channel. Several structural differences are also identified that could relate to the unique function and selectivity of SecA2. Suppressor mutations of a
secA2
mutant map to the surface of SecA2 and help identify functional regions of SecA2 that may promote interactions with SecYEG.
NEW ZEALAND FORMULARY FOR CHILDREN–A CASE STUDY OF NATIONAL PAEDIATRIC FORMULARY DEVELOPMENT
Authors: Simpson Bryan , Reith David , Medlicott Natalie , Smith Alesha , Tilyard Murray 
Published: December 2015

BackgroundThe New Zealand Formulary for Children (NZFc) was developed to build on the New Zealand Universal List of Medicines through the addition of clinical information about medicines use in paediatrics. The structure and content of the NZFc is based on the British National Formulary for Children (BNFc) but is adapted for New Zealand practice.AimsTo adapt the BNFc to provide New Zealand healthcare professionals with information about the selection, prescribing, dispensing, and administration of medicines; to link the clinical information with subsidy and registration status of medicines; to incorporate additional resources according to local requirements.MethodsThe initial release (November, 2013) of the NZFc was adapted from the latest version of the BNFc focusing on relevance to NZ practice. The BNFc prescribing notes were reviewed by medical specialists and clinical pharmacists before review and approval by an editorial advisory board. The BNFc drug monographs were compared to New Zealand approved Medicine Datasheets (NZAMD) and tailored to reflect New Zealand approved indications and doses. The NZFc is an on-line publication provided as open access within New Zealand. When off-label uses were identified, validation was undertaken using appropriate alternate resources.ResultsThe NZFc was successfully developed and user statistics indicate that it is being utilised by the New Zealand health sector with 172796 visitors (February 2015). Also, monthly page views have steadily increased from 35944 (November 2013) to 216064 (February 2105).ConclusionThe project demonstrated that it is possible to adapt the BNFc for application in other countries.
NOVEL APP FOR SMARTPHONES AND TABLETS TO OPTIMIZE AND STANDARDIZE DRUG PRESCRIPTIONS IN NEONATES
Authors: Rodieux Frederique , Sanduja Sachin , Pfister Marc , Anker John Van den 
Published: December 2015

BackgroundNeonates in intensive care units (NICU) are highly vulnerable to medication errors. Studies indicate that junior doctors have a prescribing error rate of up to 10%. Prescription errors result in overdosing or underdosing and affect clinical outcomes. Advances in mobile technology have brought opportunities for creating bedside decision support tools, including smartphone applications (apps). Ownership of smartphones and tablets by medical professionals is 80% or higher. The most commonly used apps amongst medical trainees are drug prescription guidelines and calculators.ResultsNovel drug prescription app based on reference texts such as the British National Formulary for children (BNFc), neonatal formulary seventh edition (NNF7) and the Red Book of the American Academy of Pediatrics. This app permits neonatologists to easily access up-to-date dose information and quickly calculate individual dose based on a patient's characteristics (e.g. weight, age, serum creatinine value).ConclusionApps for smartphones and tablets can serve as bedside decision support tools in neonatology. Pharmacometric modeling can be built in such apps to leverage historical and current patient data, individualize dosing strategies, and further optimize treatment benefits for neonates. Furthermore such applications may facilitate standardization of drug prescriptions among the nine NICUs in Switzerland.
NOVEL APP FOR PRACTICAL DOSING OF COMBINATION ANTIRETROVIRAL THERAPY IN PEDIATRIC PATIENTS WITH HIV/AIDS
Authors: Anker J.N.Y. van den , Sanduja S. , Ferrer Kathleen , Rakhmanina N. , Pfister Marc 
Published: December 2015

BackgroundCombination antiretroviral therapy (ART) of HIV infection in pediatric patients requires lifetime daily administration of a minimum of three antiretroviral drugs (ARVs). A wide range of dosing regimens is used in these patients. Dosing errors are common and may result in ARVs overdosing with associated toxicities orARVs underdosing resulting in the development of viral resistance. Attempts have been made to produce compact ARVs dosing charts, but have not been successful due to the complexity of regimens, ARV drug-drug interactions and compatibility restrictions. Advances in mobile technology have brought new opportunities for creating dosing support tools, including smartphone applications (Apps). In middle and low income countries, most affected by HIV epidemic,smartphones and tablets are widespread among medicalprofessionals. A mobile Appthat produces correct pediatric ARVs dosing, warnings for compatibility and most important drug interactions,has the potential to significantly improve the quality of ART in HIV-infected children.MethodsUsing reference ARVs guidelines from the 2014 Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection by the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children and 2013 World Health Organization pediatric HIV treatment guidelines we have developed a novel drug prescription App for pediatric ART.ResultsA noveldrug prescription App, based on up to date references, permits health care providers to easily access up-to-date dosing information and quickly calculate individualdoses of all ARVsbased on a patient's characteristics (e.g. weight, height, age, serum creatinine value). Most importantly, the App can be easily updated and synchronized remotely, allowing for timelydelivery of most important pediatric ARVs dosing updates.ConclusionThe smartphone App for pediatric ARVs can serve as an important healthcare worker support tool in the treatment of HIV-infected infants and children. Pharmacometric modelingcan be built in such App to leverage resistance and clinical patient data, individualize dosing strategies particularly for co-morbidities and optimize ART outcome. Most importantly, in the era of the global scale up of pediatric ART and task shifting of ART management to nursing staff, this App can have significant capacitating effect on the healthcare workforce.
SAFETY OF ACE INHIBITORS IN CHILDREN WITH HEART FAILURE
Authors: der Meulen Marijke van , Läer Stephanie , Castro Cristina , Khalil Feras , de Wildt Saskia , Dalinghaus Michiel , Jovanović Ida , Bajčetić Milica , Lagler Florian 
Published: December 2015

BackgroundACE inhibitors (ACE-I) are a cornerstone in the treatment of children with heart failure. Little is known on the pharmacokinetics (PK) and pharmacodynamics (PD) of enalapril in children. LENA trials will investigate a novel child-appropriate solid drug formulation of enalapril and obtain PK, PD and safety data. For this study clear safety cut-offs need to determined.AimTo review the literature on safety of ACE-I in paediatric heart failure.MethodsWe searched electronic databases and reference lists of relevant studies. Inclusion criteria were 1. Randomized Controlled Trials (RCT), Controlled trials (CT), case reports or retrospective cohorts. 2. Patients under 18 years with congestive heart failure. 3. Any kind of ACE-I 4. Outcome measures: Mortality, hypotension, renal failure, hyperkalaemia, liver enzyme rise, cough, neutropenia.ResultsWe assessed 12 of 593 articles as relevant: 2 RCTs, 5 CTs, 3 retrospective cohort studies and 2 case reports on a total of 734 children with heart failure. Systematic analyses was hampered by the heterogeneity of the study designs. In summary, we identified renal failure, hypotension and hyperkalemia as the most important side effects. Renal failure was found in 80 patients (11%), hypotension in 33 (4,5%) and hyperkalemia in 5 (0,7%). Five studies (n= 315 children) suggest that young age and low weight increases the risk of renal failure.ConclusionsRenal failure, hypotension and hyperkalemia are the most reported adverse events in children on an ACE-I for heart failure. We defined strict adjusting- and stopping rules for enalapril based on an Acute Kidney Injury scale, b. on values of systolic blood pressure and on c. serum levels potassium.The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA).
INDUSTRIAL ACTIVITY REVIEW OF THE FRENCH NETWORK OF PEDIATRIC CLINICAL INVESTIGATION CENTERS (FN-PCIC) 2008–2013
Authors: Maksooud Elsa , Jacqz-Aigrain Evelyne 
Published: December 2015

IntroductionThe French Network of Pediatric Clinical Investigations Centers (FN-PCIC) created in 2000 includes today 16 CIC grouped under the auspices of the INSERM and the corresponding public university hospitals. In response to the European pediatric regulation published in 2007, all pharmaceuticals laboratories, in order to complete their drug profile, must conduct pediatric clinical trials according to the Pediatric Clinical Investigation Plan and validated by the European Medicines Agency (EMA). This network plays a major role in facilitating and optimizing the conduction of nation-wide pediatric clinical trials. Therefore, the PN-CIC plays a major role to response to this acute demand in the pediatric field. The purpose of this review is to sum up the activity of the FN-PCIC between 2008 and 2013 and to analyze the impact of the European regulation.MethodsOnly the industrial protocols will be analyzed, for every protocol a certain number of information was collected such as the pharmaceutical industry, the therapeutic fields, the phase of the study, the duration of the study, the methodology, and the number of patients needed.Results261 protocols were active during this period by 90 different sponsors. 218 were interventional studies and 43 were observational or non-drug studies (registers, post-AMM). The number of active studies was at 127 in 2013 compared to 76 in 2008. Furthermore, the total number of participations were 242 for 16 CIC in 2013 compared to 110 in 2008. The mean inclusion rate was 87%. The percentage of the common studies rises from 36% in 2008 to 50% in 2013. In addition, the feasibility study demands increased and were as high as 57, an average of one demand per week The inclusion percentage calculated using the data of the closed studies is at 87%. The therapeutic fields concerned were nephrology and oncology (15%), then neurology and pneumology (13%).ConclusionActivity increased, linked to the national coverage now including 16 centers and high quality procedures to perform pediatric research trials under high ethical and quality standards.
THE CLINICAL UTILITY AND SAFETY OF A MODEL-BASED PATIENT-TAILORED DOSE REGIMEN OF VANCOMYCIN IN NEONATES
Authors: Leroux Stéphanie , Biran Valérie , Lopez Emmanuel , Madeleneau Doriane , Jacqz-Aigrain Evelyne , Zhao Wei 
Published: December 2015

Background and objectivePharmacokinetic modeling approach is often applied to evaluate antimicrobials in neonates. However, the clinical application of the model-based personalized antimicrobial therapy is still limited. Our objective is to evaluate the clinical utility and safety of the model-based patient-tailored dosing of vancomycin in neonates.MethodsA model-based vancomycin dosing calculator, which was developed using the pharmacokinetic information from our previously published population pharmacokinetic model, has been integrated into the routine clinical care in 3 NICUs (Cochin, Robert Debré and Clocheville Hospitals) between June 2012 and November 2014. The target attainment rate was selected as the endpoint for evaluating the clinical utility. The percentage of patients achieving the target concentration of vancomycin was calculated using the first TDM samples taken 6–24 hours after starting vancomycin treatment. The safety evaluation was focused on nephrotoxicity, which was evaluated based on changes in serum creatinine concentration from a baseline value obtained within the 48 hours of starting vancomycin treatment.ResultsA total of 190 neonates were included. The mean of the 190 first TDM vancomycin concentrations was 20.0 mg/L (10th-90th percentiles: 13.1–27.6). After receiving patient-tailored doses, the target attainment rate was 71.6% (n=136) within the range of 15–25 mg/L (90.5%, n=172, within the range of 10–30 mg/L). None of the included patients has developed vancomycin-related nephrotoxicity.ConclusionThe present work provides an evidence-based study to demonstrate the clinical utility and safety of a model-based patient-tailored dose regimen of vancomycin in neonates. The results from population pharmacokinetic study were successfully integrated in neonatal clinical practice to individualise vancomycin therapy.
SPONTANEOUS ADVERSE DRUG REACTION REPORTS FOR NEONATES AND INFANTS IN THE UK 2001–2010
Authors: Hawcutt Dan , Maqsood Hannah , Gomberg Simon , Riordan Andrew , Turner Mark 
Published: December 2015

AimsThe UK Medicines and Healthcare products Regulatory Agency (MHRA) runs a national spontaneous reporting system (Yellow Card Scheme [YCS]) to collect ‘suspected' adverse drug reaction (ADR) data. We aim to describe the Yellow card reports received for patients aged ≤1 year for a 10 year period and assess their utility.MethodsData on all ADRs reported via the YCS in Infants aged ≤1 years from the years 2001–10 were supplied by the MHRA.ResultsIn total, 3217 suspected ADRs were reported to the YCS between 2001–10 for infants age ≤1 year (Neonates n=97, vaccinations n=2673, infant [neither neonate nor vaccine] n=477). Overall only 0.88 YC per day were received by the MHRA with a male preponderance (Male 50.3%, Female 45.7%); only 25 (0.8%) YC reports stated a gestational age for the affected infant. The medications most frequently reported as suspected of causing an ADR were Swine Flu Vaccine (neonates n=8), Neisseria meningitides (vaccinations n=693) and oseltamivir (infants n=37). Reports associated with vaccinations followed the expected trends. ADRs highlighted by regulators for neonatal and infant populations are not represented in the YCs received by the regulator.Conclusions The frequency of YCS reports for those ≤1 year is low, with less than 1 per day overall. Neonates are poorly represented, and recording of gestational age is very limited. The YCS appears to be more effective for spontaneous reporting of vaccination-related ADRs in infants than for other medications. Action is required to improve reporting of suspected ADRs that affect neonates and infants.
PARACETAMOL DISPOSITION IN YOUNG WOMEN: BOTH PREGNANCY AND TOOLS TO AVOID PREGNANCY MATTER
Authors: Allegaert Karel , Peeters Mariska Y , Beleyn Bjorn , Smits Anne , Kulo Aida , van Calsteren Kristel , Deprest Jan , AJ Knibbe Catherijne 
Published: December 2015

IntroductionIn this pooled study, we focused on the population pharmacokinetic profile of intravenous paracetamol metabolism and its covariates in young women, including during pregnancy and postpartum.MethodsPopulation PK parameters using non-linear mixed effect modelling were estimated in a pooled dataset of plasma and urine PK studies in 69 young women [47 at delivery, 8/47 again 10–15 weeks after delivery (early postpartum), and 7/8 again one year after delivery (late postpartum), 22 healthy female volunteers with or without oral contraceptives].ResultsPopulation PK parameters were estimated based on 815 plasma samples and 101 urine collections. Compared to healthy female volunteers (reference group) not on oral contraceptives, being at delivery was the most significant covariate for clearance to paracetamol glucuronide (F=2.03), while women in early postpartum had decreased paracetamol glucuronidation clearance (F=0.55). Women on contraceptives showed increased paracetamol glucuronidation clearance (F=1.46). The oestradiol level did not further affected this model. Being at delivery did not prove significant for clearance to paracetamol sulphate, but was higher in pregnant women who delivered preterm (<37 weeks, F=1.34) compared to term delivery and non-pregnant women. Finally, clearance of unchanged paracetamol was dependent on urine flow rate.ConclusionsCompared to healthy female volunteers, the urine paracetamol glucuronidation elimination in young women is affected by pregnancy (higher), early postpartum (lower) or exposure to oral contraceptives (higher). This may be of relevance to predict variability in glucuronidation activity in young women and to predict fetal exposure to paracetamol and its metabolites.
EXTREMELY PREMATURE NEONATES EXHIBIT INSULIN RESISTANCE
Authors: Salis Emma R , Reith David M , Broadbent Roland S , Wheeler Benjamin J , Medlicott Natalie J 
Published: December 2015

IntroductionPreterm birth disrupts normal timing of physiological adaptation of insulin secretion putting premature neonates at risk of abnormal glucose homeostasis. The insulin/C-peptide (I/CP) ratio gives an indication of insulin clearance but has not been reported in neonates. Premature neonates have significantly higher fasting levels of GLP-1 than adults that increase even further with feeding.AimsTo determine I/CP and insulin/blood glucose level (I/BGL) ratios in neonates and the effect of postmenstrual age (PMA) on these measures. To determine GLP-1 concentrations in never-fed versus fed neonates.MethodsPlasma samples were obtained from 102 neonates admitted to Dunedin Hospital NICU. Plasma was analysed for insulin and C-peptide using chemiluminescent kits (Invitron, UK), GLP-1 and glucagon using ELISA (BioCore Pty Ltd, Australia). Statistical analyses were performed using Stata/IC (v11.2).ResultsThe PMA range was 24–51.3 weeks. The median I/CP ratio was 0.44, 95% CI (0.44, 0.61). The median I/BGL ratio was 9.3, 95% CI (8.2, 10.6). Linear regressions of ln-transformed data were performed. I/CP and I/BGL ratios were significantly affected by PMA (p<0.01). Negative correlations were found (r=−0.21 and −0.35 for I/CP and I/BGL respectively, p<0.01) and I/CP changed around 34 weeks. Insulin concentrations were negatively correlated (r=−0.38, p<0.01) with increasing PMA. ANOVA showed higher GLP-1 concentrations (p=0.011) in fed versus never-fed neonates.ConclusionsThese findings indicate insulin resistance in premature neonates prior to 34 weeks gestation. The significantly higher GLP-1 concentrations in fed neonates confirm that GLP-1 increases with the establishment of feeding.
HOW SAFE IS ON-LABEL DRUG USE IN PAEDIATRICS? THE CASE OF FIRST GENERATION H1-ANTIHISTAMINES
Authors: Bruyne Pauline De , Boussery Koen , Christiaens Thierry , Mehuys Els , Winckel Myriam Van 
Published: December 2015

BackgroundFor obvious reasons, much attention has recently been paid to off-label prescriptions in paediatrics. However, on-label prescribing can cause health issues too: we discuss the case of first generation H1-antihistamines (FGAs). These have been in use for over 70 years, for a variety of indications such as relief of allergic conditions, cough and insomnia.Materials and methodsThe FGAs were listed using their International Nonproprietary Names (INN). For each formulation, the information of the Summary of Product Characteristics issued in five selected European countries (Belgium, France, Germany, the Netherlands and United Kingdom) was collected. This was plotted against the published evidence on efficacy and safety of each FGA.Results16 different FGAs are currently marketed in single-drug oral preparations in the evaluated countries. When investigating each drug separately, a huge variability in labelled indications, licensing age for paediatric use, and availability characteristics in the different countries is observed. Most of the indications are not supported by evidence from published clinical trials.ConclusionBoth health care professionals and consumers generally assume that all approved H1-antihistamines have been shown to be efficacious and safe, but many in this class – in particular those introduced before 1985 – have not been optimally studied. This might explain the inconsistencies in indications and licensing ages of the evaluated drugs in different countries. Moreover, many of the antihistamines are sold over the counter, which may contribute to overuse. Such overuse can be a serious problem, as sedation is a known side effect of all FGAs.