bluuebunny/crossref_metadata_2025 huggingface dataset:
WHAT IS THE APPROPRIATE VALGANCICLOVIR DOSAGE IN CHILDREN WITH SOLID ORGAN TRANSPLANT? A PROSPECTIVE PHARMACOKINETIC STUDY
Authors: Peled Orit , Ashkenazi-Hoffnung Liat , Rom Eran , Bilavsky Efraim , Bernfeld Yael , Dorfman Lev , Amir Jacob , Brandriss Nurit , Bar-Haim Adina , Berkovitch Matitiahu
Published: December 2015

Valganciclovir (VGC) is extensively used for cytomegalovirus (CMV) infection treatment and prophylaxis after solid organ transplantation (SOT). VGC dosing is problematic in children. VGC has variable absorption and is renally excreted. AUC0-24 of 40–60 mcg·h/L is a predictive pharmacokinetic parameter of efficacy and safety. Dosing based on manufacturer recommendations is supra-therapeutic in most cases. A few published dosing algorithms result in AUC out of range.

Objective

To prospectively validate a VGC administration dosing regimen and compare it to other dosing algorithms.

Methods

Children after SOT at Schneider Children's Medical Center, the largest tertiary pediatric center in Israel, were prospectively studied, starting Dec 2014. The dosing regimen was derived from Seattle Children's Hospital guidelines; 14–16 mg/kg/dose. For impaired renal function, stratified dose reduction was used. Blood was withdrawn at steady state: 2, 5 and 10 hours post dosing. Drug level was analyzed by HPLC.

Results

Nine children aged 52 (37–137) [median; (inter-quartile range)] months were studied. Four had renal and 5 had liver transplantation. VGL dose administered was 16.67 (16.42–17.72) mg/kg/dose. AUC was 20.56 (18.7–22.7) mcg·h/L. AUC was sub-therapeutic in 8 children. Manufacturer-recommended dose in our patients was suppose to be 43.5 (24.84–46.7) mg/kg/dose, significantly higher than in our study (p=0.004). Dosing based upon Asberg et al study (Pediatr. Transplantation 2014;18:103) –25.5 (19.38–25.5) mg/kg/dose, was significantly higher than in our study (p=0.009).

Conclusions

VGC dosing regimen in SOT children is still not clear. There are significant differences between dosing algorithms. More studies are needed. Recruitment of patients to our study continues.
EFFECT OF FLUSH VOLUME ON GENTAMICIN DELIVERY THROUGH UMBILICAL VENOUS CATHETERS
Authors: Lala Anita , Reith David , Broadbent Roland , Medilcott Natalie
Published: December 2015

Background

Intravenous gentamicin is frequently prescribed for the treatment of early-onset sepsis to premature neonates. Background infusion rate and flush volume are known to influence gentamicin delivery and we aimed to further quantify these factors.

Methods

Intravenous infusions were designed to simulate gentamicin delivery through umbilical venous catheters with a constant background flow rate of 0.5 mL/hr. Doses of gentamicin (2 mg or 5 mg) were administered by bolus injection over 3–5 minutes followed by a flush of 0.9% saline (1 mL or 2 mL). Samples were collected at 5 minute intervals for 1 hour and analysed by high pressure liquid chromatography.

Results

Complete recovery of 2 mg and 5 mg doses was observed following administration of both flush volumes. Of the 2.15 mg recovered when a 1 mL flush is used, 85% (standard deviation, SD, 3.1%) was collected by 10 minutes and 93% (SD 1.4%) over the first 30 minutes. When a 2 mL flush is given, 99% (SD 0.5%) of the 1.88 mg administered dose is recovered in 10 minutes. Following a 5 mg intended dose, 93% (SD 3.4%) is recovered at 10 minutes and 97% (SD 2%) in 30 minutes after a 1 mL flush, compared to 99% (SD 0.6%) recovery at 10 minutes with a 2 mL flush.

Conclusion

Simulated gentamicin delivery by bolus injection into slow-flowing neonatal central lines resulted in >90% dose recovery at 1 hour. Additionally, discrepancies between intended and actual gentamicin dose, and retrograde flow of dye was observed.
SPONTANEOUS ADVERSE DRUG REACTION REPORTS FOR TRANSPLACENTAL AND TRANSMAMMARY ROUTES IN THOSE ≤1 YEAR IN THE UK 2001–2010
Authors: Russell Nicki-Jayne , Turner Mark , Hawcutt Dan
Published: December 2015

Aims

The 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 describe the Yellow card reports received for patients aged ≤1 year across a 10 year period (2001–10).

Methods

The MHRA supplied YCS data for patients aged ≤1 year from the years 2001–2010. This analysis includes all reports involving transplacental, transmammary, or paternal route of exposure. Data were analysed to include number, type and outcome of ADRs.

Results

There were 279 reports, including 249 different medications (a YCS may contain ≥1 medication). The most commonly reported drugs were fluoxetine (n=25), citalopram (n=22), paroxetine (n=19) and venlafaxine (n=19). The outcome of the ADR was death in 10.4% of reports. Doctors reported 75.4% (n=215) of reports, however only 3.9% (n=11) were from the parent/carer. Gender was documented in 66% cases and gestation was stated in only 15% of reports.

Conclusions

Despite many women requiring medications in pregnancy and while lactating, very few YCS reports were received over a 10 year period. Current MHRA advice is for all suspected ADRs in children following transplacental or transmammary exposure to be reported. Strategies to improve reporting in this neglected population are urgently needed.
MIDAZOLAM FOR IMAGING PROCEDURAL SEDATION IN CHILDREN: A SYSTEMATIC REVIEW
Authors: Alotaibi Badriyah , Choonara Imti , Sammons Helen
Published: December 2015

Aim

To evaluate effectiveness and safety of midazolam as a sedative agent in children undergoing imaging procedures.

Methods

A systematic literature review on MEDLINE (1948–September 2014), EMBASE (1980–September 2014), International Pharmaceutical Abstracts (1970 to September 2014) and PubMed database (until September 2014) in all languages. Studies evaluating midazolam use in children undergoing imaging procedural sedation were included if they reported efficacy and/or safety outcomes.

Results

25 studies, in 6145 patients, evaluated adverse events (AEs). Dosage and route ranged from 0.1 to 0.6 mg/kg for intravenous route, 0.15 to 0.45 mg/kg for intranasal, 0.5 to 0.6 mg/kg for oral and 0.3 to 1 mg/kg for rectal administration. The most common AE was hypoxia (74), in 3.6 per 100 patients. Cases were mild (SpO2 90–95%) in 42 (2.1% incidence) and moderate (SpO2<90%) in 32 cases (1.5%), with no severe cases. All were completely reversible after simple airway manoeuvres. Vomiting was the second most frequently, 1 per 100 patients. Two serious AEs occurred, both myoclonic-like movements of upper and lower extremities requiring medical interventions and hospitalisation. 24 studies, in 3717 patients, evaluated efficacy. Procedural success rates ranged from 0% to 100%, median 86%. Success was higher for shorter procedures; CT scan (median 86.7%) versus for MRI (median 59%).

Conclusions

Midazolam for imaging procedural sedation has a low incidence of AEs, the occurrence of hypoxia emphasises the importance of monitoring during sedation. The success rate is variable, with shorter procedures seeing better results.
SHORT-COURSE ORAL CORTICOSTEROID TOXICITY IN CHILDREN
Authors: Ajebab Fahad , Choonara Imti , Conroy Sharon
Published: December 2015

Background

Multiple studies have evaluated and reported adverse drug reactions (ADRs) of corticosteroids. Short course oral corticosteroids are commonly used in children in the management of conditions such as asthma exacerbations. This systematic review aimed to identify the most common and serious ADRs associated with short courses of oral corticosteroids and to determine their relative risk levels in children.

Methods

A literature search of the databases: Embase, Medline, International Pharmaceutical Abstracts, CINAHL, the Cochrane Library and PubMed was performed to identify all studies where corticosteroids had been administered to paediatric patients ranging from 28 days to 18 years of age for up to and including 14 days of treatment. Each database was searched from their earliest dates to December 2013. All types of studies that provided clear information on adverse events were included with no language restrictions. Quality assessments were performed on all studies by two independent reviewers.

Results

Thirty eight studies met the inclusion criteria. These studies represented 3202 children and contained reports of 847 adverse events. The three most frequent ADRs were vomiting, increased blood pressure and behavioural changes. The incidence rates of these three ADRs were 6.3%, 8.5% and 4.8% of patients respectively. The risk of vomiting was greater with oral prednisolone than oral dexamethasone with a relative risk of 3.62 (95% CI 1.89, 6.95; P=0.0001). Prednisolone sodium phosphate was reported to cause vomiting less frequently than other prednisolone dosage forms (P=0.047). HPA axis suppression was detected in 43 of 53 patients who were tested. The relative risk of oral prednisolone to cause HPA axis suppression compared with inhaled steroids was 9.95 (95% CI 1.73, 53.03; P=0.010). Infection was one of the most serious ADRs, one child died after contracting a varicella zoster infection.

Conclusions

Vomiting, increased blood pressure and behavioural changes were the most frequent ADRs seen when short-course oral corticosteroids were given to children. In addition, infection was the most serious ADR. The majority of children who receive short course oral corticosteroids will experience HPA axis suppression.
HOW DOES THE IN VIVO BILIARY ELIMINATION OF DRUGS CHANGE WITH AGE? EVIDENCE FROM CLINICAL DATA USING A SYSTEMS PHARMACOLOGY APPROACH
Authors: Johnson Trevor , Rowland-Yeo Karen , Jamei Masoud , Rostami-Hodjegan Amin
Published: December 2015

There is little information on the development of biliary drug elimination (BE) with age. The aims of this study were to collate literature data on the pharmacokinetics of biliary excreted drugs used in paediatrics and to apply a Physiologically Based Pharmacokinetic model to predict their systemic clearance (CLiv) across this age range.

Drug parameters for azithromycin, ceftriaxone and digoxin were collated from the literature and validated against adult clinical data in Simcyp (V14R1). The change in CLiv with age was simulated in the paediatric model and compared to the observed data; the ontogeny function associated with BE was optimised in order to recover the age-related CLiv.

For azithromycin (79% BE) a fraction of adult biliary excretion activity of 15% had to be assumed to be able to predict accurately the CL of the drug in neonates (24 to 28 weeks GA) whilst 100% activity was apparent by 7 months. For ceftriaxone (51% BE) full biliary excretion activity appeared to be present at full term birth. Finally, for digoxin (25% BE), a fraction of adult biliary excretion activity of 10% had to be assumed to predict the CL of the drug at birth whilst 100% activity was present by The ontogeny of BE for all three drugs appears to be rapid and reach adult levels at birth or in the first few months of postnatal age. More research is required in this area particularly on the ontogeny of specific canalicular transporters in humans.
POPULATION PHARMACOKINETICS AND DOSING OPTIMIZATION OF TEICOPLANIN IN CHILDREN WITH MALIGNANT HAEMATOLOGICAL DISEASE
Authors: Zhao Wei , Zhang Daolun , Storme Thomas , Baruchel André , Declèves Xavier , Jacqz-Aigrain Evelyne
Published: December 2015

Background

Children with haematological malignancy represent an identified subgroup of the paediatric population with specific pharmacokinetic parameters. In these patients, inadequate empirical antibacterial therapy may result in infection-related morbidity and increased mortality, making optimization of the dosing regimen essential. As paediatric data are limited, our aim was to evaluate the population pharmacokinetics of teicoplanin in order to define the appropriate dosing regimen in this high-risk population.

Methods

The current dose of teicoplanin was evaluated in children with haematological malignancy. Population pharmacokinetics of teicoplanin was analysed using NONMEM software. The dosing regimen was optimised based on the final model.

Results

Eighty-five children (age range: 0.5 to 16.9 years) were included. Therapeutic drug monitoring and opportunistic samples (n=143) were available for analysis. With the current recommended dose of 10 mg/kg/day, 41 children (48%) had sub-therapeutic steady-state trough concentrations (Css,min<10 mg/liter). A two-compartment pharmacokinetic model with first-order elimination was developed. Systematic covariate analysis identified that bodyweight (size) and creatinine clearance significantly influenced teicoplanin clearance. The model was validated internally. Its predictive performance was further confirmed in an external validation. In order to reach the target AUC of 750 mg·h/L, 18 mg/kg was required for infants, 14 mg/kg for children and 12 mg/kg for adolescents. A patient-tailored dose regimen was further developed and reduced variability in AUC and Css,min values compared to the mg/kg-basis dose, making the modelling approach an important tool for dosing individualization.

Conclusions

This first population pharmacokinetic study of teicoplanin in children with haematological malignancy provided evidence-based support to individualize teicoplanin therapy in this vulnerable population.
PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS FOR ADULT AND PAEDIATRIC CHRONIC HEART FAILURE PATIENTS USING THE EXAMPLE OF CARVEDILOL TREATED PATIENTS
Authors: Rasool Muhammad , Khalil Feras , Läer Stephanie
Published: December 2015

Background

In chronic heart failure (CHF), the changes in organ blood flows can significantly affect the metabolism of drugs with high hepatic extraction. Physiologically based pharmacokinetic modelling (PBPK) can be utilized to predict clearances of high extraction drugs like carvedilol in CHF. The adult PBPK-CHF model after its evaluation in adults, can be scaled to pediatrics using population based PBPK simulator.

Methods

After a literature search for model input parameters, two-PBPK models were developed which differed only on the basis of clearance as, model-1 was based on human liver and intestinal microsomes clearance and model-2 was based on cytochrome-P450 clearances. Developed models were evaluated in healthy adults and in adult CHF patients, after incorporation of reduced organ blood flows. The evaluated adult CHF models were finally scaled to pediatric CHF patients using population based simulator Simcyp®. A two-fold error range for the ratios(Obs/Pred) of the pharmacokinetic parameters was used for model evaluation.

Results

The prediction results from both models were within the 2-fold error range but the initial absorption phase after oral drug application was slightly over predicted with model-1 on the other hand, the model-2 efficiently captured the oral absorption phase. The CL/F ratios(Obs/Pred) were clearly improved after incorporation of reduced organ blood flows in adult CHF patients. In pediatrics CHF patients, improvement in predictions were seen only in adolescents above 17 years of age, staged with NYHA system of classification.

Conclusion

There was a clear link between reduced organ blood flows and reduced carvedilol clearance in adult patients with CHF. It was suggested that Ross scoring system in pediatrics was not well correlated with organ blood flow reductions as the NYHA classification system. Due to the mechanistic nature of the developed models, they can be extended to other drugs with high hepatic extraction.

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) and from the Faculty Development Program BZ University Multan, Pakistan.
INVASIVENESS OF PHARMACOKINETIC STUDIES IN CHILDREN–A SYSTEMATIC REVIEW
Authors: Altamimi Mohammed , Sammons Helen , Choonara Imti
Published: December 2015

Objectives

To compare the invasiveness of recent pharmacokinetic (PK) studies with older studies. The extent of this will be evaluated by analysing the number of samples and volume of blood collected in each study.

Methods

A systematic literature review was performed to identify papers describing number of samples and volume of blood collected in studies of children (aged 0–18 years). The following databases were searched: Medline (1946 to May 2014), Embase (1974 to May 2014), International Pharmaceutical Abstracts (1970 to May 2014), CINAHL and Cochrane library. The keywords were “preterm neonate*” OR term neonate*” OR “neonate*” OR “new-born*” OR “child*” OR children OR “p*ediatric* OR “infant*” OR “adolescent*” AND “pharmacokinetic*” OR blood OR plasma OR specimen OR serum OR blood sampling OR blood sample*. Patients were grouped according to the guidelines of the International Conference of Harmonization (ICH), i.e. preterm neonates, term neonates, infants (28 days-under 2 years), children (2–11 years) and adolescents (12−≤18 years).

Results

A total of 501 paediatric PK studies were identified between 1974 and 2014. Eighty eight studies were conducted between 1980 and 1990 (old studies), while 193 were conducted between 2004 and 2014 (new studies). Significantly more blood samples per child were collected in the old (median 8 [IQR: 6–11]) versus the new studies (median 7 [IQR: 5–9]) (p=0.002). In children the frequency of blood sampling was significantly higher in old studies (median 9 [IQR: 7–12]) compared to new studies (p=0.0002), but in the other age categories, there were no significant differences. There was no significant difference in the individual sample volume collected at each time point between two periods (p=0.913). However the total volume of blood collected for the study was significantly more in the old period (median=14 ml IQR [4.5–27.5 ml]) than in the new studies (median=11 ml, IQR [6–18 ml]) (p=0.040).

Conclusions

Significantly more blood samples and larger total volumes of blood were taken in the old studies compared to new PK studies involving children. No major difference in the individual sample volume was seen.
AVAILABILITY OF PAEDIATRIC-EVALUATED FORMULATIONS IN SERBIA
Authors: Božić Bojana , Stupar Sanja , Stupar Duško , Bajčetić Milica
Published: December 2015

Background/Objective

A lack of appropriately evaluated medicines for paediatric population is a major problem as it often leads to inadequate treatment of children. The aim of this study was to investigate the availability of paediatric formulations labelled for children up to the age of 12 years old in Serbia in 2013, as well as the availability of paediatric medicines reimbursed by the Republic Health Insurance Fund (RFZO). The availability of paediatric formulations in Serbia is also compared with the ‘Model List of Essential Medicines for Children’ by World Health Organization's (WHO).

Methods

Sources of information about medicines were: the Summary of Product Characteristics (SmPc), RFZO Drug Lists, WHO Model Lists of Essential Medicines for Children, and Serbia's official drug registry, editions 2013.

Results

In Serbia only 49% (496) of INN drugs were suitable for children of which only 66% were licensed for paediatric use. Majority of licensed drugs were parenteral formulations, 57%, followed by drugs for local use, 28%, and formulations for oral use, 23%. The lowest availability of medicines was for children 0–27 days old. From the total number of licensed medicines for children up to 12 years old, the Republic Fund for Health Insurance covers 64% of drugs and from each therapeutic group at least one medicine is reimbursed by fund. The availability of WHO essential medicines for children in Serbia was 51%, from which 92% were licensed for paediatric use.

Conclusion

Our study showed that from already unsatisfactory number of available drugs for children only 66% is licensed. Limited availability of paediatric medicines for all ages of this population and for a broad range of therapeutic areas still represents a cause for concern in our country.
RANDOMISED CONTROLLED TRIALS OF CHRONIC PAIN IN CHILDREN AND ADOLESCENTS: A SYSTEMATIC REVIEW
Authors: Boulkedid Rym , Abdou Armiya Yousouf , Desselas Emilie , Monegat Marlène , Alberti Corinne , Kaguelidou Florentia
Published: December 2015

Background

Approximately 15 to 30% of children and adolescents suffer from daily pain persistent over more than 3 months and there is evidence supporting that the prevalence of chronic pain is steadily increasing in this population. Chronic pain is known to have a negative impact on children's development and social behaviour, leading often to severe psychological distress and physical disability. We reviewed medical literature to assess the characteristics and quality of randomized controlled trials (RCTs) on pharmacological and non-pharmacological therapies in chronic and recurrent pain in the paediatric population.

Methods

We performed a systematic search of PubMed, Embase and the Cochrane Library up to March 2014. Bibliographies of relevant articles were also hand-searched. We included all RCTs that involved children and adolescents (age 0 to 18 years) and evaluated the use of a pharmacological agent or a non-pharmacological approach in the context of chronic or recurrent pain. The latter was defined as pain persisting for more than 3 months. Methodological quality was evaluated using the Cochrane Risk of Bias Tool. Two reviewers independently assessed studies for inclusion and evaluated methodological quality.

Results

A total of 52 randomized controlled trials were selected and included in the analysis. The majority were conducted in single hospital institutions, with no information on study funding. Median sample size was 45 (34–57) participants. Almost 50% of the RCTs included both adults and children with a median age at inclusion of 13 years. Non-pharmacological approaches were more commonly tested whereas evaluation of pharmacological agents concerned less than 30% of RCTs. Abdominal pain and headache were the most common types of chronic pain experienced among trial participants. Overall, the methodological quality was poor and did not parallel the number of RCTs that increased over the years. The risk of bias was high or unclear in 70% of the trials.

Conclusions

This is the first systematic review of RCTs conducted to evaluate pharmacological and non-pharmacological therapies in chronic and recurrent pain in children and adolescents. Although, management of pain in adults has significantly improved over the years due to the evaluation of numerous analgesic therapies, our results highlight the existing knowledge gap with regards to children and adolescents. Therapeutic strategies, in particular pharmacological agents, applied to relieve chronic or recurrent pain in children and adolescents are not evaluated through high quality RCTs. The need to improve analgesic therapy in children and adolescents with chronic pain is still unmet. We discuss possible research constraints and challenges related to this fact as well as adequate methodologies to circumvent them.
EVALUATION OF THE APPLICABILITY OF A CHILD-APPROPRIATE HIGH THROUGHPUT HPLC-MS/MS METHOD FOR THE DETERMINATION OF ENALAPRIL AND ENALAPRILAT IN SMALL SAMPLE VOLUMES OF SERUM AND URINE WITHIN A GCLP-COMPLIANT ENVIRONMENT
Authors: Schäfer Julia , Burckhardt Björn B. , Tins Jutta , Läer Stephanie
Published: December 2015

Background

Heart failure is a life-threatening disease in neonates up to adolescents. The angiotensin-converting enzyme inhibitor enalapril is a recommended therapy in paediatric heart failure, although it is not labelled for patients Objective: Proof of concept of the paediatric tailored assays by verification of the reliable conduct of sample analysis according to international bioanalytical guidelines and determination of enalapril and its active metabolite enalaprilat in the LENA phase I study.

Methods

All LENA phase I samples were analysed applying the developed high throughput analysis for enalapril and enalaprilat via HPLC-MS/MS. According to the established LENA GCLP-compliant quality system, the evaluation of all study samples was conducted by using freshly prepared quality standards to obtain calibration curves of enalapril and enalaprilat in serum and urine.

Results

In total, 22 calibration curves in serum and 7 in urine were required to investigate all samples of the phase I study of LENA. All 29 calibration curves complied with the limits of FDA and EMA bioanalytical guidelines and the applicability of the established high throughput method in the GCLP environment was proven. About 2100 study samples were successfully determined within 26 days.

Conclusion

The developed paediatric tailored high throughput HPLC-MS/MS analysis proved its applicability in a GCLP-compliant environment and is suitable for the upcoming phase II and phase III studies of the LENA project focussing on paediatric patients.

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).
Sudden onset unilateral sensorineural hearing loss after rabies vaccination
Authors: Okhovat Saleh , Fox Richard , Magill Jennifer , Narula Antony
Published: December 2015

A 33-year-old man developed profound sudden onset right-sided hearing loss with tinnitus and vertigo, within 24 h of pretravel rabies vaccination. There was no history of upper respiratory tract infection, systemic illness, ototoxic medication or trauma, and normal otoscopic examination. Pure tone audiograms (PTA) demonstrated right-sided sensorineural hearing loss (thresholds 90–100 dB) and normal left-sided hearing. MRI internal acoustic meatus, viral serology (hepatitis B, C, HIV and cytomegalovirus) and syphilis screen were normal. Positive Epstein-Barr virus IgG, viral capsid IgG and anticochlear antibodies (anti-HSP-70) were noted. Initial treatment involved a course of high-dose oral prednisolone and acyclovir. Repeat PTAs after 12 days of treatment showed a small improvement in hearing thresholds. Salvage intratympanic steroid injections were attempted but failed to improve hearing further. Sudden onset sensorineural hearing loss (SSNHL) is an uncommon but frightening experience for patients. This is the first report of SSNHL following rabies immunisation in an adult.
Emergency general surgery ‘Hot Clinics’ reduce admission rates and duration of inpatient stay
Authors: Th'ng Francesca , Skouras Christos , Paterson-Brown Alice , Ravindran Rajan , Lamb Peter , de Beaux Andrew , Paterson-Brown Simon , Mole Damian J
Published: December 2015

Objective

To determine the impact of a ‘Hot Clinic’ (HC) on emergency general surgery patient flow-through.

Design

Prospective service evaluation study.

Setting

HC is a four-bedded area coordinated by a specialist nurse. The HC consultant sees emergency patients referred from the emergency department, general practitioners or those in preceding 24 h considered suitable for interim discharge while awaiting investigations and HC reassessment.

Patients

All patients with acute abdominal pain were evaluated in three 4 week groups: before (group 1), 1 month (group 2) and 6 months after the HC was introduced (group 3). Interhospital transfers, intrahospital ward referrals and trauma patients were excluded.

Intervention

Introduction of consultant-led surgical HC every weekday afternoon.

Main outcome measures

Proportion of patients admitted under general surgeons, length of inpatient stay and the proportion of patients referred again within 3 months were investigated.

Results

1409 patients were referred, of which 1061 met the inclusion criteria: 307 in group 1, 326 in group 2 and 428 in group 3. There was no difference in gender distribution (p=0.759). Inpatient admissions were significantly reduced (85.0% vs 78.2% vs 54.4%; p<0.001) and the inpatient duration of stay was significantly shorter after HC introduction (median (IQR) (95% CI) 63.8 (29.0–111.6) (51.8 to 72.8) hours vs 48.8 (21.7–101.2) (42.0 to 55.6) hours vs 47.7 (20.9–92.7) (42.8 to 56.9) hours; p=0.011).

Conclusions

Emergency general surgery HCs are associated with significant reductions in admission rates and inpatient bed occupancy. This service redesign has the potential to dramatically relieve pressure on acute surgical services.
Explosive solutions of stochastic viscoelastic wave equations with multiplicative noises
Authors: Liang Fei , Zhu Hai , Liao Xiuwu
Published: December 2015

In this paper, a class of stochastic nonlinear viscoelastic wave equations driven by multiplicative noises is considered. By an appropriate energy inequality, we provide sufficient conditions such that the local solutions of the stochastic equations blow up with positive probability or are explosive in an [Formula: see text] sense. Moreover, we also derive the estimates of upper bound of the blow-up time.
Quantifying Different Tactile Sensations Evoked by Cutaneous Electrical Stimulation Using Electroencephalography Features
Authors: Zhang Dingguo , Xu Fei , Xu Heng , Shull Peter B. , Zhu Xiangyang
Published: December 2015

Psychophysical tests and standardized questionnaires are often used to analyze tactile sensation based on subjective judgment in conventional studies. In contrast with the subjective evaluation, a novel method based on electroencephalography (EEG) is proposed to explore the possibility of quantifying tactile sensation in an objective way. The proposed experiments adopt cutaneous electrical stimulation to generate two kinds of sensations (vibration and pressure) with three grades (low/medium/strong) on eight subjects. Event-related potentials (ERPs) and event-related synchronization/desynchronization (ERS/ERD) are extracted from EEG, which are used as evaluation indexes to distinguish between vibration and pressure, and also to discriminate sensation grades. Results show that five-phase P1–N1–P2–N2–P3 deflection is induced in EEG. Using amplitudes of latter ERP components (N2 and P3), vibration and pressure sensations can be discriminated on both individual and grand-averaged ERP ([Formula: see text]). The grand-average ERPs can distinguish the three sensations grades, but there is no significant difference on individuals. In addition, ERS/ERD features of mu rhythm (8–13[Formula: see text]Hz) are adopted. Vibration and pressure sensations can be discriminated on grand-average ERS/ERD ([Formula: see text]), but only some individuals show significant difference. The grand-averaged results show that most sensation grades can be differentiated, and most pairwise comparisons show significant difference on individuals ([Formula: see text]). The work suggests that ERP- and ERS/ERD-based EEG features may have potential to quantify tactile sensations for medical diagnosis or engineering applications.
Minimal representations for 6-dimensional nilpotent Lie algebra
Authors: Rojas Nadina
Published: December 2015

Given a Lie algebra [Formula: see text], let [Formula: see text] and [Formula: see text] be the minimal dimension of a faithful representation and nilrepresentation of [Formula: see text], respectively. In this paper, we give [Formula: see text] and [Formula: see text] for each nilpotent Lie algebra [Formula: see text] of dimension [Formula: see text] over a field [Formula: see text] of characteristic zero. We also give a minimal faithful representation and nilrepresentation in each case.
Some special cyclic codes of length 2n
Authors: Singh Manjit , Batra Sudhir
Published: December 2015

The explicit expressions of generator polynomials of cyclic codes of length [Formula: see text] over finite fields are obtained. The coefficients of these generator polynomials and check polynomials are obtained through modular Lucas sequences. Further, using these polynomials, self-dual, reversible and self-orthogonal cyclic codes of length [Formula: see text] are classified.
Laser facilitates vaccination
Authors: Wang Ji , Li Peiyu , Chen Xinyuan , Wu Mei X.
Published: December 2015

Development of novel vaccine deliveries and vaccine adjuvants is of great importance to address the dilemma that the vaccine field faces: to improve vaccine efficacy without compromising safety. Harnessing the specific effects of laser on biological systems, a number of novel concepts have been proposed and proved in recent years to facilitate vaccination in a safer and more efficient way. The key advantage of using laser technology in vaccine delivery and adjuvantation is that all processes are initiated by physical effects with no foreign chemicals administered into the body. Here, we review the recent advances in using laser technology to facilitate vaccine delivery and augment vaccine efficacy as well as the underlying mechanisms.
Changing and unchanging Open Packing: Edge removal
Authors: Hamid I. Sahul , Saravanakumar S.
Published: December 2015

In a graph [Formula: see text], a nonempty set [Formula: see text] is said to be an open packing set if no two vertices of [Formula: see text] have a common neighbor in [Formula: see text] The maximum cardinality of an open packing set is called the open packing number and is denoted by [Formula: see text]. In this paper, we examine the effect of [Formula: see text] when [Formula: see text] is modified by deleting an edge.
Radiolarian evidence for the age of chert blocks from the Upper Cretaceous ophiolitic mélange unit of the Erakh area, Armenia
Authors: Danelian T. , Asatryan G. , Sahakyan L. , Avagyan A. , Galoyan G.
Published: December 2015

Two new and relatively well-preserved radiolarian faunas were extracted from blocks included in the Cretaceous ophiolitic mélange unit that crops out in the Erakh area south of Yerevan, Armenia. One of these radiolarian assemblages was extracted from cherts that are in stratigraphic contact with variolitic lavas. This radiolarian assemblage suggests a late Aalenian to middle Bajocian age (Unitary Association Zones 2–3) based on the co-occurrence of the species
Parasaturnalis diplocyclis
(Yao) and
Transhsuum hisuikyoense
(Isozaki & Matsuda). A second radiolarian assemblage was obtained from a block, several metres thick, of alternating pelagic limestones and cherts. It was characterized by the co-occurrence of the species
Hemicryptocapsa capita
Tan and
Dicerosaturnalis dicranacanthos
(Squinabol). The presence of these two species within the same assemblage correlates with Unitary Association Zone 17 and these samples are therefore assigned to the late Valanginian. These results suggest that submarine volcanic activity took place during the late Aalenian–middle Bajocian interval and that mixed carbonate and siliceous ooze accumulated during the late Valanginian. Previous biochronological data on Radiolaria from the Erakh mélange and the Vedi ophiolite are reviewed and their implications for the geodynamic and palaeoenvironmental evolution of the Tethyan ocean in Armenia are discussed.
The role of pre-break-up heat flow on the thermal history of a transform margin
Authors: Nemčok M. , Henk A. , Molčan M.
Published: December 2015

The paper focuses on the Romanche transform margin on the African side of the Equatorial Atlantic, and draws from thermomechanical numerical modelling and subsequent GIS-based thermal history grid processing.

Our modelling indicates that the early post-break-up thermal history of the transform margin is controlled by the cooling patterns of the adjacent pull-apart terrains, the pre-rift heat-flow regime, laterally passing seafloor spreading centres, and cooling of the newly accreted oceanic crust in two corridors located in front of and behind the spreading centres.

The pre-rift thermal regime controls the background heat flow on top of which the thermal transients develop. If it is cold, the transient anomalies are very distinct on this background. If it is warm, the transient anomalies tend to blend in with background heat flow much better. The most prominent anomalies are related to thinning in the pull-apart terrains located between transforms. They are up to three times wider than anomalies related to the laterally passing spreading centre, the anomaly of which becomes no wider than 20–25 km. Together with oceanic crust accreted in corridors in front of and behind the passing centre, its heat transfer into the transform margin tends to slow down the cooling of the syn-break-up anomalies developed in the pull-apart terrains by rifting.
Transform-margin model of hydrocarbon migration: the Guyana–Suriname case study
Authors: Nemčok M. , Rybár S. , Ekkertová P. , Kotulová J. , Hermeston S. A. , Jones D.
Published: December 2015

The study focuses on the Guyana–Suriname transform margin, utilizing well and reflection seismic data. Both datasets allow the permeability stratigraphy to be interpreted. It consists of areally extensive reservoir horizons separated by intraformational shale horizons and erosional unconformities. The youngest strata are deformed by the two generations of gravity glides, which took place fairly late in post-break-up history.

Hydrocarbon shows from wells indicate that strata deformed by gravity glides are the only sedimentary packages where the vertical hydrocarbon migration dominates. Clusters of oil and gas shows have random spatial distribution in respective reservoir horizons within gravity glides. The base of the rock volume with dominating vertical migration is determined by the detachment horizon of the gravity-glide system. However, the areas unaffected by gravity glides are dominated by lateral migration, causing zonal distribution of oil and gas shows. Oil shows occur in wells penetrating the proximal margin and gas shows are found in wells penetrating the distal margin in respective reservoir horizons. Both sets are fed by the source rock occurring in the oceanic basin and the adjacent distal margin. The best example of this situation is provided by the Paleocene–Eocene reservoirs.
Structure of the Demerara passive-transform margin and associated sedimentary processes. Initial results from the IGUANES cruise
Authors: Loncke L. , Maillard A. , Basile C. , Roest W. R. , Bayon G. , Gaullier V. , Pattier F. , Mercier de Lépinay M. , Grall C. , Droz L. , Marsset T. , Giresse P. , Caprais J. C. , Cathalot C. , Graindorge D. , Heuret A. , Lebrun J. F. , Bermell S. , Marcaillou B. , Sotin C. , Hebert B. , Patriat M. , Bassetti M. A. , Tallobre C. , Buscail R. , Durrieu de Madron X. , Bourrin F.
Published: December 2015

The IGUANES cruise took place in May 2013 on the R/V
L'Atalante
along the Demerara passive transform margin off French Guiana and Surinam. Seismic, multibeam and chirp acquisitions were made. Piston cores were collected for pore geochemistry and sedimentology. A mooring was deployed on the sea-bottom for 10 months (temperature, salinity, turbidity and current measurements). This new dataset highlights the lateral variability of the 350 km-long Guiana–Surinam transform margin due to the presence of a releasing bend between two transform segments. The adjacent Demerara Plateau is affected by a 350 km-long giant slide complex. This complex initiated in Cretaceous times and was regularly reactivated until recent times. Since the Miocene, contourite processes seem to be active due to the onset of the North Atlantic Deep Water (NADW) bottom current. A main NADW water vein flows towards SE, eroding slide headscarps and allowing the deposition of contourite drifts. Numerous depressions looking like comet tails or comet scours record this flow. Some of those were interpreted before the cruise as active pockmarks. Pore geochemistry and core analysis do not show any evidence of present-day gas seepage.
A Causal Approach to the Study of TCP Performance
Authors: Hours Hadrien , Biersack Ernst , Loiseau Patrick
Published: December 2015

Communication networks are complex systems whose operation relies on a large number of components that work together to provide services to end users. As the quality of these services depends on different parameters, understanding how each of them impacts the final performance of a service is a challenging but important problem. However, intervening on individual factors to evaluate the impact of the different parameters is often impractical due to the high cost of intervention in a network. It is, therefore, desirable to adopt a formal approach to understand the role of the different parameters and to predict how a change in any of these parameters will impact performance.

The approach of causality pioneered by J. Pearl provides a powerful framework to investigate these questions. Most of the existing theory is non-parametric and does not make any assumption on the nature of the system under study. However, most of the implementations of causal model inference algorithms and most of the examples of usage of a causal model to predict intervention rely on assumptions such linearity, normality, or discrete data.

In this article, we present a methodology to overcome the challenges of working with real-world data and extend the application of causality to complex systems in the area of telecommunication networks, for which assumptions of normality, linearity and discrete data do no hold. Specifically, we study the performance of TCP, which is the prevalent protocol for reliable end-to-end transfer in the Internet. Analytical models of the performance of TCP exist, but they take into account the state of network only and disregard the impact of the application at the sender and the receiver, which often influences TCP performance. To address this point, we take as application the file transfer protocol (FTP), which uses TCP for reliable transfer. Studying a well-understood protocol such as TCP allows us to validate our approach and compare its results to previous studies.

We first present and evaluate our methodology using TCP traffic obtained via network emulation, which allows us to experimentally validate the prediction of an intervention. We then apply the methodology to real-world TCP traffic sent over the Internet. Throughout the article, we compare the causal approach for studying TCP performance to other approaches such as analytical modeling or simulation and and show how they can complement each other.
What Can Plasticity Contribute to Insect Responses to Climate Change?
Authors: Sgrò Carla M. , Terblanche John S. , Hoffmann Ary A.
Published: December 2015

Plastic responses figure prominently in discussions on insect adaptation to climate change. Here we review the different types of plastic responses and whether they contribute much to adaptation. Under climate change, plastic responses involving diapause are often critical for population persistence, but key diapause responses under dry and hot conditions remain poorly understood. Climate variability can impose large fitness costs on insects showing diapause and other life cycle responses, threatening population persistence. In response to stressful climatic conditions, insects also undergo ontogenetic changes including hardening and acclimation. Environmental conditions experienced across developmental stages or by prior generations can influence hardening and acclimation, although evidence for the latter remains weak. Costs and constraints influence patterns of plasticity across insect clades, but they are poorly understood within field contexts. Plastic responses and their evolution should be considered when predicting vulnerability to climate change—but meaningful empirical data lag behind theory.
Profound hyperglycemia in knockout mutant mice identifies novel function for POU4F2/Brn-3b in regulating metabolic processes
Authors: Bitsi Stavroula , Ali Houda , Maskell Lauren , Ounzain Samir , Mohamed-Ali Vidya , Budhram-Mahadeo Vishwanie S.
Published: December 2015

The POU4F2/Brn-3b transcription factor has been identified as a potentially novel regulator of key metabolic processes. Loss of this protein in Brn-3b knockout (KO) mice causes profound hyperglycemia and insulin resistance (IR), normally associated with type 2 diabetes (T2D), whereas Brn-3b is reduced in tissues taken from obese mice fed on high-fat diets (HFD), which also develop hyperglycemia and IR. Furthermore, studies in C2C12 myocytes show that Brn-3b mRNA and proteins are induced by glucose but inhibited by insulin, suggesting that this protein is itself highly regulated in responsive cells. Analysis of differential gene expression in skeletal muscle from Brn-3b KO mice showed changes in genes that are implicated in T2D such as increased glycogen synthase kinase-3β and reduced GLUT4 glucose transporter. The GLUT4 gene promoter contains multiple Brn-3b binding sites and is directly transactivated by this transcription factor in cotransfection assays, whereas chromatin immunoprecipitation assays confirm that Brn-3b binds to this promoter in vivo. In addition, correlation between GLUT4 and Brn-3b in KO tissues or in C2C12 cells strongly supports a close association between Brn-3b levels and GLUT4 expression. Since Brn-3b is regulated by metabolites and insulin, this may provide a mechanism for controlling key genes that are required for normal metabolic processes in insulin-responsive tissues and its loss may contribute to abnormal glucose uptake.
CTRP3 deficiency reduces liver size and alters IL-6 and TGFβ levels in obese mice
Authors: Wolf Risa M. , Lei Xia , Yang Zhi-Chun , Nyandjo Maeva , Tan Stefanie Y. , Wong G. William
Published: December 2015

C1q/TNF-related protein 3 (CTRP3) is a secreted metabolic regulator whose circulating levels are reduced in human and rodent models of obesity and diabetes. Previously, we showed that CTRP3 infusion lowers blood glucose by suppressing gluconeogenesis and that transgenic overexpression of CTRP3 protects mice against diet-induced hepatic steatosis. Here, we used a genetic loss-of-function mouse model to further address whether CTRP3 is indeed required for metabolic homeostasis under normal and obese states. Both male and female mice lacking CTRP3 had similar weight gain when fed a control low-fat (LFD) or high-fat diet (HFD). Regardless of diet, no differences were observed in adiposity, food intake, metabolic rate, energy expenditure, or physical activity levels between wild-type (WT) and Ctrp3-knockout (KO) animals of either sex. Contrary to expectations, loss of CTRP3 in LFD- or HFD-fed male and female mice also had minimal or no impact on whole body glucose metabolism, insulin sensitivity, and fasting-induced hepatic gluconeogenesis. Unexpectedly, the liver sizes of HFD-fed Ctrp3-KO male mice were markedly reduced despite a modest increase in triglyceride content. Furthermore, liver expression of fat oxidation genes was upregulated in the Ctrp3-KO mice. Whereas the liver and adipose expression of profibrotic TGFβ1, as well as its serum levels, was suppressed in HFD-fed KO mice, circulating proinflammatory IL-6 levels were markedly increased; these changes, however, were insufficient to affect systemic metabolic outcome. We conclude that, although it is dispensable for physiological control of energy balance, CTRP3 plays a previously unsuspected role in modulating liver size and circulating cytokine levels in response to obesity.
Oxidation and Corrosion Behavior of Nanolaminated MAX‐Phase Ti2AlC Film Synthesized by High‐Power Impulse Magnetron Sputtering and Annealing
Authors: Fu Jianjian , Zhang Teng Fei , Xia Qixun , Lim Sung-Hwan , Wan Zhixin , Lee Taeg-Woo , Kim Kwang Ho
Published: December 2015

Nanolaminated MAX‐phase Ti2AlC thin films were synthesized by high‐power impulse magnetron sputtering (HiPIMS) from a MAX‐phase Ti2AlC target. The amorphous matrix Ti‐Al‐C films were deposited at room temperature, while the MAX‐phase Ti2AlC films were obtained through annealing process of the as‐deposited amorphous matrix films. The microstructure, oxidation resistance, and corrosion behavior of these two films were comparatively investigated. The results indicated that the MAX‐phase Ti2AlC films had superior antioxidation and anticorrosion properties than the amorphous matrix Ti‐Al‐C films, which is attributed to the rapid formation of dense Al2O3 layer on the top of MAX‐phase Ti2AlC films because of the rapid diffusion of Al atoms in the typical nanolaminated structure of MAX phase.