bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long‐term treatment with pegvisomant for acromegaly: a 10‐year experience
Authors: Ramos‐Leví Ana M. , Bernabeu Ignacio , Álvarez‐Escolá Cristina , Aller Javier , Lucas Tomás , de Miguel Paz , Rodríguez‐Cañete Leticia , Sampedro‐Núñez Miguel A. , Halperin Irene , Puig‐Domingo Manuel , Marazuela Mónica 
Published: December 2015

SummaryBackgroundEfficacy of the GH‐receptor antagonist pegvisomant (PEG) has differed between preclinical and observational studies mainly due to dose adjustment and IGF‐I normalization criteria. An escape phenomenon has also been described, but its definition and underlying causes have not been fully established.ObjectiveTo re‐evaluate the outcomes of long‐term PEG in a series of previously published patients and analyse the escape phenomenon.MethodsWe reviewed all patients with acromegaly resistant to SSA in whom PEG was started as monotherapy, who had been included in a previous publication. We prospectively evaluated 64 (56·3% women) from six tertiary care referral hospitals in Spain, for whom data as of June 2014 were available. Escape to PEG was defined as confirmed loss of biochemical control (IGF‐I >1·2xULN), after at least 6 months of previous control with a stable dose of PEG.ResultsPatients were followed up for 13·0 (5·9–34·8) years since diagnosis, and 9·0 (4·1–10·4) years since the first administration of PEG. Fifty‐one (89·5%) patients had an adequate IGF‐I control at the last follow‐up visit, 9 of them without treatment. Tumour growth was reported in 6 of 64 cases (9·4%), none of whom had received prior radiotherapy (P = 0·011). Seven patients died during follow‐up. We found 16 escapes in 10 patients (15·6%). We identified potential underlying causes in 9 cases (tumour regrowth, previous treatment modifications, concomitant menopause and change in testosterone administration). The reason was unknown in 7 escapes, which occurred in 6 patients (9·4%). All patients, except one, achieved subsequent biochemical control after treatment adjustment.ConclusionsWe reassure the efficacy and safety of long‐term PEG. An escape phenomenon may occur, but it can be overcome by adjusting therapy.
New insulin glargine 300 U/ml versus glargine 100 U/ml in Japanese adults with type 1 diabetes using basal and mealtime insulin: glucose control and hypoglycaemia in a randomized controlled trial (EDITION JP 1)
Authors: Matsuhisa M. , Koyama M. , Cheng X. , Takahashi Y. , Riddle M. C. , Bolli G. B. , Hirose T. ,   on behalf of the EDITION JP 1 study group
Published: December 2015

AimTo compare efficacy and safety of new insulin glargine 300 U/ml (Gla‐300) with that of insulin glargine 100 U/ml (Gla‐100) in Japanese adults with type 1 diabetes.MethodsThe EDITION JP 1 study (NCT01689129) was a 6‐month, multicentre, open‐label, phase III study. Participants (n = 243) were randomized to Gla‐300 or Gla‐100 while continuing mealtime insulin. Basal insulin was titrated with the aim of achieving a fasting self‐monitored plasma glucose target of 4.4–7.2 mmol/l. The primary endpoint was change in glycated haemoglobin (HbA1c) over 6 months. Safety measures included hypoglycaemia and change in body weight.ResultsGla‐300 was non‐inferior to Gla‐100 for the primary endpoint of HbA1c change over the 6‐month period {least squares [LS] mean difference 0.13 % [95 % confidence interval (CI) −0.03 to 0.29]}. The annualized rate of confirmed (≤3.9 mmol/l) or severe hypoglycaemic events was 34 % lower with Gla‐300 than with Gla‐100 at night [rate ratio 0.66 (95 % CI 0.48–0.92)] and 20 % lower at any time of day [24 h; rate ratio 0.80 (95 % CI 0.65–0.98)]; this difference was most pronounced during the first 8 weeks of treatment. Severe hypoglycaemia was infrequent. The basal insulin dose increased in both groups (month 6 dose: Gla‐300 0.35 U/kg/day, Gla‐100 0.29 U/kg/day). A between‐treatment difference in body weight change over 6 months favouring Gla‐300 was observed [LS mean difference −0.6 kg (95 % CI −1.1 to −0.0); p = 0.035]. Adverse event rates were comparable between the groups.ConclusionsIn Japanese adults with type 1 diabetes using basal plus mealtime insulin, less hypoglycaemia was observed with Gla‐300 than with Gla‐100, particularly during the night, while glycaemic control did not differ.
Brivaracetam, a selective high‐affinity synaptic vesicle protein 2A (SV2A) ligand with preclinical evidence of high brain permeability and fast onset of action
Authors: Nicolas Jean‐Marie , Hannestad Jonas , Holden Daniel , Kervyn Sophie , Nabulsi Nabeel , Tytgat Dominique , Huang Yiyun , Chanteux Hugues , Staelens Ludovicus , Matagne Alain , Mathy François‐Xavier , Mercier Joël , Stockis Armel , Carson Richard E. , Klitgaard Henrik 
Published: December 2015

SummaryObjectiveRapid distribution to the brain is a prerequisite for antiepileptic drugs used for treatment of acute seizures. The preclinical studies described here investigated the high‐affinity synaptic vesicle glycoprotein 2A (SV2A) antiepileptic drug brivara‐cetam (BRV) for its rate of brain penetration and its onset of action.BRVwas compared with levetiracetam (LEV).MethodsIn vitro permeation studies were performed using Caco‐2 cells. Plasma and brain levels were measured over time after single oral dosing to audiogenic mice and were correlated with anticonvulsant activity. Tissue distribution was investigated after single dosing to rat (BRVandLEV) and dog (LEVonly). Positron emission tomography (PET) displacement studies were performed in rhesus monkeys using theSV2APETtracer [11C]UCB‐J. The time course ofPETtracer displacement was measured following single intravenous (IV) dosing withLEVorBRV. Rodent distribution data and physiologically based pharmacokinetic (PBPK) modeling were used to compute blood–brain barrier permeability (permeability surface area product,PS) values and then predict brain kinetics in man.ResultsIn rodents,BRVconsistently showed a faster entry into the brain thanLEV; this correlated with a faster onset of action against seizures in audiogenic susceptible mice. The higher permeability ofBRVwas also demonstrated in human cells in vitro.PBPKmodeling predicted that, followingIVdosing to human subjects,BRVmight distribute to the brain within a few minutes compared with approximately 1 h forLEV(PSof 0.315 and 0.015 ml/min/g forBRVandLEV, respectively). These data were supported by a nonhuman primatePETstudy showing fasterSV2A occupancy byBRVcompared withLEV.SignificanceThese preclinical data demonstrate thatBRVhas rapid brain entry and fast brainSV2A occupancy, consistent with the fast onset of action in the audiogenic seizure mice assay. The potential benefit ofBRVfor treatment of acute seizures remains to be confirmed in clinical studies.
Modes of functional biodiversity control on tree productivity across the European continent
Authors: Ratcliffe Sophia , Liebergesell Mario , Ruiz‐Benito Paloma , Madrigal González Jaime , Muñoz Castañeda Jose M. , Kändler Gerald , Lehtonen Aleksi , Dahlgren Jonas , Kattge Jens , Peñuelas Josep , Zavala Miguel A. , Wirth Christian 
Published: December 2015

AbstractAimThe relative contribution of community functional diversity and composition to ecosystem functioning is a critical question in ecology in order to enable better predictions of how ecosystems may respond to a changing climate. However, there is little consensus about which modes of functional biodiversity are most important for tree growth at large spatial scales. Here we assessed the relative importance of climate, functional diversity and functional identity (i.e. the community mean values of four key functional traits) for tree growth across the European continent, spanning the northern boreal to the southern Mediterranean forests.LocationFinland, Germany, Sweden, Spain and Wallonia (Belgium).MethodsUsing data from five European national forest inventories we applied a hierarchical linear model to estimate the sensitivity of tree growth to changes in climate, functional diversity and functional identity along a latitudinal gradient.ResultsFunctional diversity was weakly related to tree growth in the temperate and boreal regions and more strongly in the Mediterranean region. In the temperate region, where climate was the most important predictor, functional diversity and identity had a similar importance for tree growth. Functional identity was strongest at the latitudinal extremes of the continent, largely driven by strong changes in the importance of maximum height along the latitudinal gradient.Main conclusionsFunctional diversity is an important driver of tree growth in the Mediterranean region, providing evidence that niche complementarity may be more important for tree growth in water‐limited forests. The strong influence of functional identity at the latitudinal extremes indicates the importance of a particular trait composition for tree growth in harsh climates. Furthermore, we speculate that this functional identity signal may reflect a trait‐based differentiation of successional stages rather than abiotic filtering due to water or energy limitation.
Children with moderate‐high infection with Entamoeba coli have higher percentage of body and abdominal fat than non‐infected children
Authors: Zavala G. A. , García O. P. , Campos‐Ponce M. , Ronquillo D. , Caamaño M. C. , Doak C. M. , Rosado J. L. 
Published: December 2015

SummaryBackgroundIntestinal parasites, virus and bacterial infections are positively associated with obesity and adiposity in vitro and in animal models, but conclusive evidence of this relationship in humans is lacking. The aim of this cross‐sectional study was to determine differences in adiposity between infected and non‐infected children, with a high prevalence of intestinal parasitic infection and obesity.SubjectsA total of 296 school‐aged children (8.0 ± 1.5 years) from a rural area in Querétaro, Mexico, participated in this study. Anthropometry (weight, height and waist circumference) and body fat (DXA) were measured in all children. A fresh stool sample was collected from each child and analysed for parasites. Questionnaires related to socioeconomic status and clinical history were completed by caretakers.ResultsApproximately 11% of the children were obese, and 19% were overweight. The overall prevalence of infection was 61%. Ascaris lumbricoides was the most prevalent soil transmitted helminth (16%) followed by hookworm. Entamoeba coli was the predominant protozoa (20%) followed by Endolimax nana, Balantidium coli, Entamoeba histolytica/dispar, Iodamoeba bütschlii and Giardia lamblia. Children with moderate–heavy infection of E. coli had significantly higher waist circumference, waist‐to‐height ratio, body and abdominal fat than children not infected or with light‐intensity infection (p < 0.05).ConclusionThese findings raise the possibility that a moderate or heavy infection with E. coli may contribute to fat deposition and thereby have long‐term consequences on human health. Further studies are needed to better understand if E. coli contributes directly to fat deposition and possible mechanisms.
MC3R gene polymorphisms are associated with early childhood adiposity gain and infant appetite in an Asian population
Authors: Aris I. M. , Tint M. T. , Teh A. L. , Holbrook J. D. , Quah P. L. , Chong M. F.‐F. , Lin X. , Soh S. E. , Saw S.‐M. , Kwek K. , Godfrey K. M. , Gluckman P. D. , Chong Y. S. , Lek N. , Yap F. , Lee Y. S. 
Published: December 2015

SummaryBackgroundPolymorphic variants within human melanocortin‐3 receptor gene (MC3R) gene have been associated with obesity. However, its influence on infancy and early childhood adiposity has not been reported before.ObjectivesWe assessed associations between genotype at polymorphic sites within MC3R with early childhood adiposity and interaction with early childhood appetitive traits.MethodsWe studied 1090 singletons in an Asian mother–offspring cohort genotyped for MC3R and in a subgroup (n = 422) who had completed Child Eating Behaviour Questionnaires (CEBQ) at 12 months. Children were followed from birth to 48 months, and up to 10 measurements of body mass index and five measures of triceps and subscapular skin‐folds were obtained.ResultsIndependent of potential confounders, each additional MC3R minor allele copy was associated with greater body mass index standard deviation score [B{95% confidence interval}: 0.004 units/month {0.001,0.007}; p = 0.007], triceps [0.009 mm/month {0.001,0.02}; p = 0.021] and subscapular skin‐fold [0.008 mm/month {0.002,0.01}; p = 0.011] gain velocity in the first 48 months. Each additional MC3R minor allele copy was also associated with increased odds of overweight [odds ratio {95% confidence interval}: 1.48{1.17–1.88}] and obesity [1.58{1.10–2.28}] in the first 48 months. Every additional copy of MC3R minor allele was positively associated with ‘slowness‐in‐eating’ appetitive trait [0.24{0.06,0.39}, p = 0.006]; however, the relationship between ‘slowness‐in‐eating’ with adiposity gain was not statistically significant.ConclusionsOur findings support the role of MC3R genetic variants in adiposity gain during early childhood.
Genetic risk clustering increases children's body weight at 2 years of age – the STEPS Study
Authors: Mäkelä J. , Lagström H. , Pitkänen N. , Kuulasmaa T. , Kaljonen A. , Laakso M. , Niinikoski H. 
Published: December 2015

SummaryBackgroundGenetic determinants have an impact on adult weight but the association between genetic determinants and weight at young age is still poorly understood.ObjectiveThe objective of this study was to examine the association between genetic risk scores and early growth from birth to 2 years of age.MethodsGenetic risk scores of 83 adiposity‐related or obesity‐related single nucleotide polymorphisms (SNPs) (genetic risk score [GRS]83) were calculated for 1278 children. Specific phenotype score for 16 weight‐related SNPs (weightGRS) was calculated. Anthropometric data were obtained at birth, 13 months and 2 years of age.ResultsThe GRS83 was associated with weight at 13 months (β = 0.080, P = 0.015) and 2 years (β = 0.080, P = 0.017) of age and with weight gain from birth to 13 months (β = 0.069, P = 0.036) and to 2 years of age (β = 0.074, P = 0.028). At 2 years of age, the GRS83 was also associated with weight for height (β = 0.065, P = 0.046), weight‐for‐height standard deviation score (SDS) (β = 0.074, P = 0.022) and body mass index SDS (β = 0.068, P = 0.045). WeightGRS was associated with higher body weight at 13 months (β = 0.081, P = 0.014) and 2 years of age (β = 0.086, P = 0.011). The genetic effect on weight varied from 0.69 to 1.89 kg at 2 years of age according to number of risk alleles. Children with high genetic risk for adiposity were heavier than children with low genetic risk at 2 years of age (12.8 vs. 13.4 kg, P = 0.017).ConclusionThe GRS 83 revealed increased genetic risk for higher weight in children already at 13 months and 2 years of age, which may result in increased obesity risk later in life.
French Public Finances through the Financial Crisis: It's a Long Way to Recovery
Authors: André Mathias , Bozio Antoine , Guillot Malka , Paul‐Delvaux Louise 
Published: December 2015

AbstractFrance was modestly hit by the financial crisis compared with its neighbours but the recovery has been particularly slow. The shock to the public finances was nonetheless significant, and came on top of an already weak pre‐crisis fiscal position. Part of this shock is expected to be permanent and the French government has so far mostly used increases in taxation to bring borrowing under control. However, in 2014, spending cuts took over as the main tool for balancing the public finances. Despite the significant fiscal adjustments that have been required, the crisis has not been used as an opportunity for reforms. Some reforms to labour and service markets have been carried out, but there have been no radical changes. While some tax changes, such as cuts to employer social security contributions and an increase in reduced rates of VAT, have improved the efficiency of the tax system, overall the tax and benefit system continues to be plagued by complexity and a sheer lack of transparency. As the remaining effort for balancing the public finances seems likely to rely on spending cuts, the overall efficiency of the policy response to the crisis will depend in large part on how these are done.
Cyberattacks as Casus Belli: A Sovereignty‐Based Account
Authors: Smith Patrick Taylor 
Published: December 2015

AbstractSince cyberattacks are nonphysical, standard theories of casus belli — which typically rely on the violent and forceful nature of military means — appear inapplicable. Yet, some theorists have argued that cyberattacks nonetheless can constitute just causes for war — generating a unilateral right to defensive military action — when they cause significant physical damage through the disruption of the target's computer systems. I show that this view suffers from a serious drawback: it is too permissive concerning the types of actions that generate casus belli since many essentially peaceful and non‐violent mechanisms can nonetheless cause physical damage. I resolve this difficulty by developing a sovereignty‐based account of casus belli and applying it to cyberwarfare. I argue that legitimate states have a constrained right to unilaterally respond with military force to unfriendly actions that bypass or overwhelm the political deliberations of the target state in order to force a change in behaviour contrary to the determinations of the people of the target state. This new account of casus belli avoids the problems of the consequence‐based view by plausibly restricting the types of unfriendly action that give rise to casus belli and yet offers an attractive explanation for why some cyberattacks nonetheless do generate a potential right to a unilateral defensive response.
Criminalising Unknowing Defence
Authors: Uniacke Suzanne 
Published: December 2015

AbstractShould a legal plea of self‐ or third‐party defence include an ‘awareness component’ that requires that the actor was aware of the justificatory facts at the time of action? Some theorists argue that in cases of so‐called unknowing defence, where an actor in fact averts an otherwise unavoidable danger to himself or another person although unaware at the time of action that this is what he is doing, the objective facts alone should allow a plea of self‐ or third‐party defence. Cases of unknowing defence raise issues that are highly significant to the nature of justification and liability. In this article I reject some common approaches to this issue and I offer an account of why acts of unknowing defence are appropriately subject to criminal liability for the complete offence (e.g. murder).
Comprehensive antibiotic susceptibility profiling of Chilean Piscirickettsia salmonis field isolates
Authors: Henríquez P , Kaiser M , Bohle H , Bustos P , Mancilla M 
Published: December 2015

AbstractAntibiotics have been extensively used against infections produced by Piscirickettsia salmonis, a fish pathogen and causative agent of piscirickettsiosis and one of the major concerns for the Chilean salmon industry. Therefore, the emergence of resistant phenotypes is to be expected. With the aim of obtaining a landscape of the antimicrobial resistance of P. salmonis in Chile, the susceptibility profiles for quinolones, florfenicol and oxytetracycline (OTC) of 292 field isolates derived from main rearing areas, different hosts and collected over 5 years were assessed. The results allowed for the determination of epidemiological cut‐off values that were used to characterize the pathogen population. This work represents the first large‐scale field study addressing the antimicrobial susceptibility of P. salmonis, providing evidence of the existence of resistant types with a high incidence of resistance to quinolones. Remarkably, despite the amounts and frequency of therapies, our results disclosed that the issue of resistance to florfenicol and OTC is still in the onset.
Effect of Preoperative Transthoracic Echocardiogram on Mortality and Surgical Timing in Elderly Adults with Hip Fracture
Authors: Luttrell Kevin , Nana Arvind 
Published: December 2015

ObjectivesTo evaluate the effect of preoperative transthoracic echocardiogram (TTE) on mortality, postoperative complications, surgical timing, and length of stay in individuals with surgically treated hip fracture.DesignRetrospective chart review of hospital records.SettingLevel I and II trauma centers.ParticipantsIndividuals consecutively surgically treated for hip fracture (N = 694).MeasurementsDemographic and injury characteristic, operative timing, preoperative echocardiogram, complications, mortality. Primary outcome measure was in hospital, 30‐day, and 1‐year mortality. Secondary outcome measures were complications (particularly cardiovascular) and time required for medical clearance and operative treatment.ResultsPreoperative TTE was performed on 131 individuals (18.9%). There was no difference between the TTE group and the control group in hospital (3.8% vs 1.8%, P = .18), 30‐day (6.9% vs 6.6%, P = .90), or 1‐year (20.6% versus 20.1%, P = .89) mortality. There was no significant difference in major cardiac complications. Average time from admission to operative treatment was 66.5 hours in the TTE group and 34.8 hours in the control group (P < .001). Average time from admission to medical clearance was 43.2 hours in the TTE group and 12.4 hours in the control group (P < .001). The TTE group also had a significantly longer length of stay (8.68 vs 6.44 days, P < .001).ConclusionPreoperative TTE was not associated with lower mortality in elderly adults with hip fracture in the short‐ or long‐term postoperative period. TTE was associated with delayed surgical treatment and longer length of stay and resulted in no cardiac intervention (e.g., cardiac catheterization, stent, stress test).
Nurse Burnout, Nurse‐Reported Quality of Care, and Patient Outcomes in Thai Hospitals
Authors: Nantsupawat Apiradee , Nantsupawat Raymoul , Kunaviktikul Wipada , Turale Sue , Poghosyan Lusine 
Published: December 2015

AbstractPurposeThe purpose of this study was to investigate the effect of nurse burnout on nurse‐reported quality of care and patient adverse events and outcomes in Thai hospitals.MethodsCross‐sectional analysis of data from 2,084 registered nurses working in 94 community hospitals across Thailand. Data were collected through survey questionnaire, including the Maslach Burnout Inventory (MBI), which measures of nurse perceived quality of care and patient outcomes. Multiple logistic regression modeling was performed to explore associations between nurse burnout on quality of care and patient outcomes.FindingsThirty‐two percent of nurses reported high emotional exhaustion, 18% high depersonalization, and 35% low personal accomplishment. In addition, 16% of nurses rated quality of care on their work unit as fair or poor, 5% reported patient falls, 11% reported medication errors, and 14% reported infections. All three subscales of the MBI were associated with increased reporting of fair or poor quality of care, patient falls, medication errors, and infections. Every unit of increasing emotional exhaustion score was associated with a 2.63 times rise in reporting fair or poor quality of care, a 30% increase in patient falls, a 47% increase in medication errors, and a 32% increase in infection.ConclusionsFindings clearly indicate that nurse burnout is associated with increased odds of reporting negative patient outcomes. Implementing interventions to reduce nurse burnout is critical to improving patient care in Thai hospitals.Clinical RelevanceHospital administrators, nurse managers, and health leaders urgently need to create favorable work environments supporting nursing practice in order to reduce burnout and improve quality of care.