bluuebunny/crossref_metadata_2025 huggingface dataset:
Lipopolysaccharide‐binding protein cannot independently predict type 2 diabetes mellitus: A nested case‐control study
Authors: Zhou Huang , Hu Jinbo , Zhu Qibo , Yang Shumin , Zhang Yi , Gao Rufei , Liu Lulu , Wang Yue , Zhen Qianna , Lv Qiong , Li Qifu
Published: March 2015

Background

Cross‐sectional studies have reported a close association between serum lipopolysaccharide‐binding protein (LBP) and many metabolic disorders. However, no longitudinal study has explored the relationship between LBP and type 2 diabetes mellitus (T2DM). The aim of the present study was to investigate the association between serum LBP levels and the risk of developing T2DM.

Methods

A 5‐year nested case‐control study of 3510 individuals was performed as part of the Environment, Inflammation and Metabolic Diseases Study (EIMDS). Clinical data were collected at baseline. Serum levels of LBP and other biochemical factors, such as insulin and high‐sensitivity C‐reactive protein, were detected 5 years later. Subjects were diagnosed as having T2DM on the basis of results of an oral glucose tolerance test (OGTT) and 1998 World Health Organization criteria. Controls were randomly selected to match cases according to age, gender, and body mass index (BMI) in a 1:1 ratio. Odds ratios (OR) for T2DM were calculated using conditional logistic regression analysis.

Results

Over a 5‐year follow‐up period, 255 subjects developed T2DM. There was no significant difference in serum LBP levels between the T2DM and control groups at baseline (19.78 ± 6.40 versus 20.53 ± 6.99 μg/mL; P = 0.207). Subjects were divided into three groups based on tertiles of LBP concentrations (n = 170 in each group; T1 = 1.31–17.16 μg/mL LBP; T2 = 17.21–22.37 μg/mL LBP; T3 = 22.49–40.08 μg/mL LBP). There was no significant association between the risk of developing T2DM and any of the LBP tertiles in either a simple model or after adjusting for general status and biochemical factors.

Conclusion

After matching for gender, age, and BMI, LBP does not improve prediction of the development of T2DM independently.
Insulin resistance is associated with all chronic complications in type 1 diabetes
Authors: Pop Andrei , Clenciu Diana , Anghel Monica , Radu Stefania , Socea Bogdan , Mota Eugen , Mota Maria , Panduru Nicolae M. ,   RomDiane Study Group
Published: March 2015

Background

Insulin resistance (IR) is present in type 1 diabetes mellitus (T1DM) and is suggested to be related to chronic diabetic complications. The primary aim of our study was to assess IR in T1DM patients with and without chronic complications. A secondary aim was to evaluate the possible association between IR and chronic diabetic complications.

Methods

This cross‐sectional study enrolled 272 patients with T1DM. Insulin resistance was quantified using the estimated glucose disposal rate (eGDR). Associations between eGDR and each diabetes complication were first evaluated using binary logistic regression, then multiparametric logistic regression with stepwise selection of covariates. The discriminative value of eGDR was assessed by receiver operating characteristic (ROC) curve analysis.

Results

Estimated GDR was lower in patients with chronic diabetic complications (6.1 vs 6.9 mg/kg per min [P = 0.02] for retinopathy; 6.3 vs 7.3 mg/kg per min [P < 0.01] for nephropathy; 6.5 vs 7.6 mg/kg per min [P < 0.01] for neuropathy; and 5.2 vs 7.5 mg/kg per min [P < 0.01] for cardiovascular complications). In univariate analysis eGDR was associated all diabetic complications. These associations remained significant after adjustment for different variables in the final regression models. In addition, eGDR was a good discriminator for each diabetic complication, with an area under the curve between 0.609 and 0.759.

Conclusions

Patients with chronic diabetic complications are more insulin resistant than those without complications. Moreover, IR was independently associated with the presence of each chronic diabetic complication, and seems to be a good discriminator for them all.
Efficacy and safety of linagliptin in Asian patients with type 2 diabetes mellitus inadequately controlled by metformin: A multinational 24‐week, randomized clinical trial
Authors: Wang Weiqing , Yang Jinkui , Yang Gangyi , Gong Yan , Patel Sanjay , Zhang Candice , Izumoto Toshiyasu , Ning Guang
Published: March 2015

Background

Despite the increasing prevalence of type 2 diabetes mellitus (T2DM) in Asia, clinical trials for glucose‐lowering therapies are often dominated by Caucasian and/or Western populations. The present Phase III randomized placebo‐controlled double‐blind, 24‐week study evaluated the efficacy and safety of the dipeptidyl peptidase‐4 inhibitor linagliptin added to metformin in Asian T2DM patients.

Methods

In all, 306 patients (n = 265 Chinese; n = 24 Malaysian; n = 17 Filipino), aged 18–80 years with HbA1c between ≥7.0 and ≤10.0% and on metformin therapy were randomized (2:1) to either linagliptin 5 mg daily or placebo added to metformin. Antidiabetes drugs other than metformin were washed out prior to randomization. The primary endpoint was change in mean HbA1c from baseline after 24 weeks.

Results

Baseline characteristics were well‐matched between the groups (overall mean [±SD] HbA1c 8.0 ± 0.8%). Adjusted mean (±SE) HbA1c decreased in the linagliptin and placebo groups by −0.66 ± 0.05 and −0.14 ± 0.07%, respectively (placebo‐corrected difference −0.52 ± 0.09%; 95% confidence interval [CI] −0.70, −0.34; P < 0.0001). In patients with baseline HbA1c ≥8.5%, the placebo‐corrected decrease in HbA1c was −0.89 ± 0.17% (P < 0.0001). Adverse events occurred in similar proportions in the linagliptin and placebo patients (27.3% and 28.0%, respectively) and few were considered drug‐related (2.4% and 0.0%, respectively). Hypoglycemia occurred in 1.0% of patients in both groups. Linagliptin therapy was weight neutral.

Conclusions

Linagliptin 5 mg was efficacious and well tolerated over 24 weeks in Asian patients with T2DM inadequately controlled by metformin.
Efficacy of bronchoscopic biopsy for the detection of epidermal growth factor receptor mutations and anaplastic lymphoma kinase gene rearrangement in lung adenocarcinoma
Authors: Zhu Pei , Pan Qingqing , Wang Mengzhao , Zhong Wei , Zhao Jing
Published: March 2015

Background

To explore the efficacy of bronchoscopic biopsy for the detection of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangement in lung adenocarcinoma.

Methods

All patients with bronchoscopic biopsy‐proven lung adenocarcinoma at the Peking Union Medical College Hospital from January 2009 to November 2011 were enrolled. Scorpion amplification refractory mutation system (ARMS) was used to detect EGFR gene mutations and fluorescence in situ hybridization (FISH) to detect ALK rearrangement. The correlation of immunohistochemistry (IHC) results with standard methods for EGFR mutation status and ALK rearrangement were checked.

Results

Bronchoscopic specimens were successfully used to detect EGFR mutation and ALK rearrangement with success rates of 85.2% and 71.3%, respectively, in non‐small cell lung cancer patients. EGFR analysis by ARMS yielded a positive result in 35.8% (33/92) and positive ALK rearrangement was detected by FISH in 7.8% (6/77) of cases. It was more likely to be unsuccessful in patients with tumor cells less than 100/high power field and the ratio tumor numbers in 0–10%. In EGFR‐IHC, the sensitivity and specificity of E746‐A750 deletions were 73.3% (11/15) and 93.3% (70/75), respectively, and those of L858R were 93.3% (14/15) and 93.2% (69/74), respectively. In ALK‐IHC, the sensitivity and specificity were 50% (3/6) and 100% (71/71), respectively.

Conclusions

Small bronchoscopic specimens could achieve higher successful detection rates via EGFR mutation and ALK gene rearrangement.
Mir‐23a induces telomere dysfunction and cellular senescence by inhibiting TRF2 expression
Authors: Luo Zhenhua , Feng Xuyang , Wang Haoli , Xu Weiyi , Zhao Yong , Ma Wenbin , Jiang Songshan , Liu Dan , Huang Junjiu , Songyang Zhou
Published: March 2015

Telomeric repeat binding factor 2 (TRF2) is essential for telomere maintenance and has been implicated in DNA damage response and aging. Telomere dysfunction induced by TRF2 inhibition can accelerate cellular senescence in human fibroblasts. While previous work has demonstrated that a variety of factors can regulate TRF2 expression transcriptionally and post‐translationally, whether microRNAs (miRNAs) also participate in post‐transcriptionally modulating TRF2 levels remains largely unknown. To better understand the regulatory pathways that control TRF2, we carried out a large‐scale luciferase reporter screen using a miRNA expression library and identified four miRNAs that could target human TRF2 and significantly reduce the level of endogenous TRF2 proteins. In particular, our data revealed that miR‐23a could directly target the 3′ untranslated region (3′UTR) of TRF2. Overexpression of miR‐23a not only reduced telomere‐bound TRF2 and increased telomere dysfunction‐induced foci (TIFs), but also accelerated senescence of human fibroblast cells, which could be rescued by ectopically expressed TRF2. Our findings demonstrate that TRF2 is a specific target of miR‐23a, and uncover a previously unknown role for miR‐23a in telomere regulation and cellular senescence.
The exonuclease Nibbler regulates age‐associated traits and modulates piRNA length in Drosophila
Authors: Feltzin Virzhiniya L. , Khaladkar Mugdha , Abe Masashi , Parisi Michael , Hendriks Gert‐Jan , Kim Junhyong , Bonini Nancy M.
Published: March 2015

Nibbler (Nbr) is a 3′‐to‐5′ exonuclease that trims the 3′end of microRNAs (miRNAs) to generate different length patterns of miRNAs in Drosophila. Despite its effect on miRNAs, we lack knowledge of its biological significance and whether Nbr affects other classes of small RNAs such as piRNAs and endo‐siRNAs. Here, we characterized the in vivo function of nbr by defining the Nbr protein expression pattern and loss‐of‐function effects. Nbr protein is enriched in the ovary and head. Analysis of nbr null animals reveals adult‐stage defects that progress with age, including held‐up wings, decreased locomotion, and brain vacuoles, indicative of accelerated age‐associated processes upon nbr loss. Importantly, these effects depend on catalytic residues in the Nbr exonuclease domain, indicating that the catalytic activity is responsible for these effects. Given the impact of nbr on miRNAs, we also analyzed the effect of nbr on piRNA and endo‐siRNA lengths by deep‐sequence analysis of libraries from ovaries. As with miRNAs, nbr mutation led to longer length piRNAs – an effect that was dependent on the catalytic residues of the exonuclease domain. These analyses indicate a role of nbr on age‐associated processes and to modulate length of multiple classes of small RNAs including miRNAs and piRNAs in Drosophila.
Process Quality Indicators Targeting Cognitive Impairment to Support Quality of Care for Older People with Cognitive Impairment in Emergency Departments
Authors: Schnitker Linda M. , Martin‐Khan Melinda , Burkett Ellen , Beattie Elizabeth R. A. , Jones Richard N. , Gray Len C. ,   The Research Collaboration for Quality Care of Older Persons: Emergency Care Panel
Published: March 2015

Objectives

The objective of this study was to develop process quality indicators (PQIs) to support the improvement of care services for older people with cognitive impairment in emergency departments (ED).

Methods

A structured research approach was taken for the development of PQIs for the care of older people with cognitive impairment in EDs, including combining available evidence with expert opinion (phase 1), a field study (phase 2), and formal voting (phase 3). A systematic review of the literature identified ED processes targeting the specific care needs of older people with cognitive impairment. Existing relevant PQIs were also included. By integrating the scientific evidence and clinical expertise, new PQIs were drafted and, along with the existing PQIs, extensively discussed by an advisory panel. These indicators were field tested in eight hospitals using a cohort of older persons aged 70 years and older. After analysis of the field study data (indicator prevalence, variability across sites), in a second meeting, the advisory panel further defined the PQIs. The advisory panel formally voted for selection of those PQIs that were most appropriate for care evaluation.

Results

In addition to seven previously published PQIs relevant to the care of older persons, 15 new indicators were created. These 22 PQIs were then field tested. PQIs designed specifically for the older ED population with cognitive impairment were only scored for patients with identified cognitive impairment. Following formal voting, a total of 11 PQIs were included in the set. These PQIs targeted cognitive screening, delirium screening, delirium risk assessment, evaluation of acute change in mental status, delirium etiology, proxy notification, collateral history, involvement of a nominated support person, pain assessment, postdischarge follow‐up, and ED length of stay.

Conclusions

This article presents a set of PQIs for the evaluation of the care for older people with cognitive impairment in EDs. The variation in indicator triggering across different ED sites suggests that there are opportunities for quality improvement in care for this vulnerable group. Applied PQIs will identify an emergency services’ implementation of care strategies for cognitively impaired older ED patients. Awareness of the PQI triggers at an ED level enables implementation of targeted interventions to improve any suboptimal processes of care. Further validation and utility of the indicators in a wider population is now indicated.
How can we promote smoking cessation in people with schizophrenia in practice? A clinical overview
Authors: Stubbs B. , Vancampfort D. , Bobes J. , De Hert M. , Mitchell A. J.
Published: March 2015

Objective

High rates of smoking and nicotine dependence are associated with increased physical comorbidity and premature death in people with schizophrenia. We conducted a clinical overview to establish how smoking cessation should be promoted in practice.

Method

Systematic clinical review of major electronic databases from inception till November 2014.

Results

A growing body of evidence supports pharmacological interventions to assist smoking cessation. The most promising evidence is for bupropion with several meta‐analyses demonstrating its effectiveness. Currently, there is limited evidence demonstrating the effectiveness of nicotine replacement therapy (NRT) and varenicline, although this is likely to be due to the paucity of research. There are no consistent data to suggest that pharmacological interventions increase adverse events. Behavioural and psychosocial interventions also demonstrate promise, particularly when combined with pharmacotherapy. Careful monitoring of antipsychotic levels (in particular clozapine) is essential, and the promotion of physical activity may be useful to negate potential weight gain and diabetes risk following smoking cessation.

Conclusion

Evidence from systematic reviews and meta‐analyses suggests that smoking cessation interventions are effective in people with schizophrenia, although more long‐term research is required. Promoting smoking cessation should be given utmost priority in clinical practice, and we offer practical strategies to facilitate this.
Perianal lichen dermatoses: A review of 60 cases
Authors: Day Tania , Bohl Tanja Gizela , Scurry James
Published: March 2015

Objectives

To determine the diagnostic range of lichen dermatoses of the perianus, their extent, and response to treatment.

Methods

We reviewed perianal biopsies submitted to a tertiary referral pathology service between January 2010 and July 2014, interpreted as ‘lichen’ or ‘lichenoid’. We collected data on patients' characteristics, referring specialty, extent of lesion and response to treatment.

Results

During the study period, 60 perianal biopsies met our inclusion criteria. The distribution of diagnoses was lichen sclerosus (LS) in 25/60 (42%), lichen simplex chronicus (LSC) in 23/60 (38%), lichen planus (LP) in 10/60 (17%), and a non‐specific lichenoid reaction in 2/60 (3%). Eleven of 25 cases of LS (44%) showed superimposed LSC. Of 10 LP cases, nine (90%) were hypertrophic and three of these showed pseudoepitheliomatous hyperplasia; none were erosive LP. Compared with patients in the LS and LSC groups, those with LP were more likely to have a localised lesion. Topical steroids were prescribed in 91% cases with treatment data available, and 98% of treated patients who returned for follow up had improved or their disease was resolved.

Conclusions

We encountered a spectrum of perianal lichen dermatoses, with LS, LP and LSC all represented. LS biopsied at the perianus is often lichenified. Hypertrophic LP is a common form of LP at the perianus.
Adverse effects of topical corticosteroids in paediatric eczema: Australasian consensus statement
Authors: Mooney Emma , Rademaker Marius , Dailey Rebecca , Daniel Ben S , Drummond Catherine , Fischer Gayle , Foster Rachael , Grills Claire , Halbert Anne , Hill Sarah , King Emma , Leins Elizabeth , Morgan Vanessa , Phillips Roderic J , Relic John , Rodrigues Michelle , Scardamaglia Laura , Smith Saxon , Su John , Wargon Orli , Orchard David
Published: March 2015

Atopic eczema is a chronic inflammatory disease affecting about 30% of Australian and New Zealand children. Severe eczema costs over AUD 6000/year per child in direct medical, hospital and treatment costs as well as time off work for caregivers and untold distress for the family unit. In addition, it has a negative impact on a child's sleep, education, development and self‐esteem. The treatment of atopic eczema is complex and multifaceted but a core component of therapy is to manage the inflammation with topical corticosteroids (TCS). Despite this, TCS are often underutilised by many parents due to corticosteroid phobia and unfounded concerns about their adverse effects. This has led to extended and unnecessary exacerbations of eczema for children. Contrary to popular perceptions, (TCS) use in paediatric eczema does not cause atrophy, hypopigmentation, hypertrichosis, osteoporosis, purpura or telangiectasia when used appropriately as per guidelines. In rare cases, prolonged and excessive use of potent TCS has contributed to striae, short‐term hypothalamic‐pituitary‐adrenal axis alteration and ophthalmological disease. TCS use can also exacerbate periorificial rosacea. TCS are very effective treatments for eczema. When they are used to treat active eczema and stopped once the active inflammation has resolved, adverse effects are minimal. TCS should be the cornerstone treatment of atopic eczema in children.
Effect of Prednisolone Administration on Patients with Unexplained Recurrent Miscarriage and in Routine Intracytoplasmic Sperm Injection: A Meta‐Analysis
Authors: Dan Song , Wei Wang , Yichao Shi , Hongbo Cheng , Shenmin Yang , Jiaxiong Wang , Hong Li
Published: March 2015

The effects of prednisolone on pregnancy outcome are open to debate. This meta‐analysis was performed to evaluate the efficiency of prednisolone administration on unexplained recurrent miscarriage (RM) and the process of assisted reproductive technology (ART). Relevant publications were searched from databases and the included randomized controlled trials (RCTs) investigated effects of prednisolone administration in women with unexplained RM or during ART. The outcomes in our analysis were measured in terms of risk ratios (RRs) with 95% confidence intervals (CI) using random effect models. This meta‐analysis was performed based on pregnancy outcomes following prednisolone treatment. This meta‐analysis provides evidence that prednisolone therapy improves pregnancy outcomes in women with idiopathic RM (live birth rate: RR 1.58, 95% CI 1.23–2.02; successful pregnancy outcome: RR 7.63, 95% CI 3.71–15.69; miscarriage rate: RR 0.42, 95% CI 0.28–0.61). Our meta‐analysis revealed a non‐significant effect of prednisolone on pregnancy outcome during intracytoplasmic sperm injection (ICSI) cycles (pregnancy rate: RR 1.02, 95% CI 0.84–1.24; clinical pregnancy rate: RR 1.01, 95% CI 0.82–1.24; implantation rate: RR 1.04, 95% CI 0.85–1.28). Prednisolone administration may improve pregnancy outcomes in women with idiopathic RM; its efficacy in women undergoing ICSI is not significant.
Estimation of Non‐Crossing Quantile Regression Curves
Authors: Cai Yuzhi , Jiang Tao
Published: March 2015

Quantile regression methods have been widely used in many research areas in recent years. However conventional estimation methods for quantile regression models do not guarantee that the estimated quantile curves will be non‐crossing. While there are various methods in the literature to deal with this problem, many of these methods force the model parameters to lie within a subset of the parameter space in order for the required monotonicity to be satisfied. Note that different methods may use different subspaces of the space of model parameters. This paper establishes a relationship between the monotonicity of the estimated conditional quantiles and the comonotonicity of the model parameters. We develope a novel quasi‐Bayesian method for parameter estimation which can be used to deal with both time series and independent statistical data. Simulation studies and an application to real financial returns show that the proposed method has the potential to be very useful in practice.
Ocular Motor Score (OMS): a clinical tool to evaluating ocular motor functions in children. Intrarater and inter‐rater agreement
Authors: Olsson Monica , Teär Fahnehjelm Kristina , Rydberg Agneta , Ygge Jan
Published: March 2015

Purpose

Ocular motor score (OMS) is a new clinical test protocol for evaluating ocular motor functions in children and young adults. OMS is a set of 15 important and relevant non‐invasive ocular motor function parameters derived from clinical practice. The aim of the study was to evaluate OMS according to intrarater and inter‐rater agreement.

Methods

Forty children aged 4–10 years, 23 girls median age 6.5 (range 4.3–9.3) and 17 boys median age 5.8 (range 4.1–9.8) were included. The ocular motor functions were assessed and scored according to the OMS protocol. The examinations were videotaped. To obtain the intrarater agreement, the first author examined and scored the children twice, first in the clinic and 2 weeks later by watching the videotape. To obtain the inter‐rater agreement, three other raters independently scored the ocular motor function of the children by watching the videotapes.

Results

The overall observed intrarater agreement was 88%, and the observed inter‐rater agreement between the three raters was 80%. For none of the subtests was there an observed intrarater agreement lower than 65%. Three of the subtests had an observed inter‐rater agreement of 65% or below.

Conclusion

Overall there was high observed intra‐ and inter‐rater agreement for the OMS test protocol. Subtests such as saccades and smooth pursuit were more difficult for raters to score similarly according the clinical OMS test protocol.
Adverse effects reported in the use of gastroesophageal reflux disease treatments in children: a 10 years literature review
Authors: Cohen Shlomi , Bueno de Mesquita Mirjam , Mimouni Francis B.
Published: March 2015

Gastroesophageal reflux (GER) is commonly observed in children, particularly during the first year of life. Pharmacological therapy is mostly reserved for symptomatic infants diagnosed with GERdisease(GERD), usually as defined in a recent consensus statement. The purpose of the present article was to review the reported adverse effects of pharmacological agents used in the treatment of paediatric GERD. We conducted this review using the electronic journal database Pubmed and Cochrane database systematic reviews using the latest 10‐year period (1 January 2003 to 31 December 2012). Our search strategy included the following keywords: omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, rantidine, cimetidine, famotidine, nizatidine, domperidone, metoclopramide, betanechol, erythromycin, baclofen, alginate. We used Pubmed's own filter of: 'child: birth–18 years'. All full articles were reviewed and we only included randomized controlled trials retrieved from our search. We addressed a summary of our search on a drug‐by‐drug basis with regard to its mechanism of action and clinical applications, and reviewed all of the adverse effects reported and the safety profile of each drug. Adverse effects have been reported in at least 23% of patients treated with histamine H2receptor antagonists (H2RAs) and 34% of those treated with proton pump inhibitors (PPIs), and mostly include headaches, diarrhoea, nausea (H2RAs and PPIs) and constipation (PPIs). Acid suppression may place immune‐deficient infants and children, or those with indwelling catheters, at risk for the development of lower respiratory tract infections and nosocomial sepsis. Prokinetic agents have many adverse effects, without major benefits to support their routine use.
Impact of CYP2C19 polymorphism on the pharmacokinetics of nelfinavir in patients with pancreatic cancer
Authors: Kattel Krishna , Evande Ruby , Tan Chalet , Mondal Goutam , Grem Jean L. , Mahato Ram I.
Published: March 2015

Aim

This study evaluated the influence of CYP2C19 polymorphisms on the pharmacokinetics of nelfinavir and its metabolite M8 in patients with pancreatic cancer.

Methods

Nelfinavir was administered orally to patients for over 10 days. The plasma concentrations of nelfinavir and M8 were measured by HPLC. The genotypes of CYP2C19*1, CYP2C19*2 and CYP2C19*3 were determined by the polymerase chain reaction‐restriction fragment length polymorphism method.

Results

Pharmacokinetic profiles of nelfinavir and M8 were characterized by wide interindividual variability. The meanCmaxof nelfinavir in CYP2C19*1/*1 patients was 3.89 ± 0.40 (n = 3) and 5.12 ± 0.41 (n = 30) µg ml–1, while that of CYP2C19*1/*2 patients was 3.60 (n = 1) and 6.14 ± 0.31 (n = 5) µg ml–1at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. For the M8 metabolite, the meanCmaxof CYP2C19*1/*1 patients was 1.06 ± 0.06 (n = 3) and 1.58 ± 0.27 (n = 30) µg ml–1, while those of CYP2C19*1/*2 patients were 1.01 (n = 1) and 1.23 ± 0.15 (n = 5) µg ml–1at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. The area under the plasma concentration–time curve (AUC(0,12 h)) values of nelfinavir for CYP2C19*1/*1 patients were 28.90 ± 1.27 and 38.90 ± 4.99 µg ml–1·h and for CYP2C19*1/*2 patients, AUC(0,12 h) was 28.20 (n = 1) and 40.22 ± 3.17 (n = 5) µg ml–1·h at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. TheCmaxof nelfinavir was significantly higher (P<0.05) in CYP2C19*1/*2 patients but there was no statistical difference in AUC(0,12 h).

Conclusion

CYP2C19*1/*2 genotype modestly affected the pharmacokinetic profiles of nelfinavir and M8 in patients with locally advanced pancreatic cancer.
Emerging drug targets for Aβ and tau in Alzheimer's disease: a systematic review
Authors: West Sophie , Bhugra Praveen
Published: March 2015

Aims

Currently, treatment for Alzheimer's disease (AD) focuses on the cholinergic hypothesis and provides limited symptomatic effects. Research currently focuses on other factors that are thought to contribute to AD development such as tau proteins and Aβ deposits, and how modification of the associated pathology affects outcomes in patients. This systematic review summarizes and appraises the evidence for the emerging drugs affecting Aβ and tau pathology in AD.

Methods

A comprehensive, systematic online database search was conducted using the databases ScienceDirect and PubMed to include original research articles. A systematic review was conducted following a minimum set of standards, as outlined by The PRISMA Group . Specific inclusion and exclusion criteria were followed and studies fitting the criteria were selected. No human trials were included in this review. In vitro and in vivo AD models were used to assess efficacy to ensure studied agents were emerging targets without large bodies of evidence.

Results

The majority of studies showed statistically significant improvement (P < 0.05) of Aβ and/or tau pathology, or cognitive effects. Many studies conducted in AD animal models have shown a reduction in Aβ peptide burden and a reduction in tau phosphorylation post‐intervention. This has the potential to reduce plaque formation and neuronal degeneration.

Conclusions

There are many emerging targets showing promising results in the effort to modify the pathological effects associated with AD. Many of the trials also provided evidence of the clinical effects of such drugs reducing pathological outcomes, which was often demonstrated as an improvement of cognition.
The potential of translational bioinformatics approaches for pharmacology research
Authors: Li Lang
Published: March 2015

The field of bioinformatics has allowed the interpretation of massive amounts of biological data, ushering in the era of ‘omics’ to biomedical research. Its potential impact on pharmacology research is enormous and it has shown some emerging successes. A full realization of this potential, however, requires standardized data annotation for large health record databases and molecular data resources. Improved standardization will further stimulate the development of system pharmacology models, using translational bioinformatics methods. This new translational bioinformatics paradigm is highly complementary to current pharmacological research fields, such as personalized medicine, pharmacoepidemiology and drug discovery. In this review, I illustrate the application of transformational bioinformatics to research in numerous pharmacology subdisciplines.
The effects of activating prior topic and metacognitive knowledge on text comprehension scores
Authors: Kostons Danny , van der Werf Greetje
Published: March 2015

Background

Research on prior knowledge activation has consistently shown that activating learners' prior knowledge has beneficial effects on learning. If learners activate their prior knowledge, this activated knowledge serves as a framework for establishing relationships between the knowledge they already possess and new information provided to them. Thus far, prior knowledge activation has dealt primarily with topic knowledge in specific domains. Students, however, likely also possess at least some metacognitive knowledge useful in those domains, which, when activated, should aid in the deployment of helpful strategies during reading.

Aims

In this study, we investigated the effects of both prior topic knowledge activation (PTKA) and prior metacognitive knowledge activation (PMKA) on text comprehension scores.

Samples & Methods

Eighty‐eight students in primary education were randomly distributed amongst the conditions of the 2 × 2 (PTKA yes/no × PMKA yes/no) designed experiment.

Results

Results show that activating prior metacognitive knowledge had a beneficial effect on text comprehension, whereas activating prior topic knowledge, after correcting for the amount of prior knowledge, did not.

Conclusions

Most studies deal with explicit instruction of metacognitive knowledge, but our results show that this may not be necessary, specifically in the case of students who already have some metacognitive knowledge. However, existing metacognitive knowledge needs to be activated in order for students to make better use of this knowledge.
Partial vs radical nephrectomy for T1 renal tumours: an analysis from the British Association of Urological Surgeons Nephrectomy Audit
Authors: Hadjipavlou Marios , Khan Fahd , Fowler Sarah , Joyce Adrian , Keeley Francis X. , Sriprasad Seshadri ,   BAUS Sections of Endourology and Oncology
Published: March 2015

Objectives

To analyse and compare data from the British Association of Urological Surgeons Nephrectomy Audit for perioperative outcomes of partial (PN) and radical nephrectomy (RN) for T1 renal tumours.

Patients and Methods

UK consultants were invited to submit data on all patients undergoing nephrectomy between 1 January and 31 December 2012 to a nationally established database using a standard pro forma. Analysis was made on patient demographics, operative technique, and perioperative data/outcome between PN and RN for T1 tumours.

Results

Overall, data from 6 042 nephrectomies were reported of which 1 768 were performed for T1 renal tumours. Of these, 1 082 (61.2%) were RNs and 686 (38.8%) were PNs. The mean age of patients undergoing PN was lower (PN 59 years vs RN 64 years; P < 0.001) and so was the WHO performance score (PN 0.4 vs RN 0.7; P < 0.001). PN for the treatment of T1a tumours (≤4 cm) accounted for 55.6% of procedures, of which 43.9% were performed using a minimally invasive technique. For T1b tumours (4–7 cm), 18.9% of patients underwent PN, in 33.3% of which a minimally invasive technique was adopted. The vast majority of RNs for T1 tumours were performed using a minimally invasive technique (90.3%). Of the laparoscopic PNs, 30.5% were robot‐assisted. There was no significant difference in overall intraoperative complications between the RN and PN groups (4% vs 4.3%; P = 0.79). However, PN accounted for a higher overall postoperative complications rate (RN 11.3% vs PN 17.6%; P < 0.001). RN was associated with a markedly reduced risk of severe surgical complications (Clavien Dindo classification grade ≥3) compared with PN even after adjusting for technique (odds ratio 0.30; P = 0.002). Operation time between RN and PN was comparable (141 vs 145 min; P = 0.25). Blood loss was less in the RN group (mean for RN 165 vs PN 323 mL; P < 0.001); however, transfusion rates were similar (3.2% vs 2.6%; P = 0.47). RN was associated with a shorter length of stay (median 4 vs 5 days; P < 0.001). A direct comparison between robot‐assisted and laparoscopic PN showed no significant differences in operation time, blood loss, warm ischaemia time, and intraoperative and postoperative complications.

Conclusions

PN was the method of choice for treatment of T1a tumours whereas RN was preferred for T1b tumours. Minimally invasive techniques have been widely adopted for RN but not for PN. Despite the advances in surgical technique, a substantial risk of postoperative complications remains with PN.
Exploring the determinants of secular decreases in dental caries among Korean children
Authors: Lee Hye‐Ju , Han Dong‐Hun
Published: March 2015

Objective

The aim of this study was to determine the contributions of sealant and water fluoridation to the time trends in dental caries from 2003 to 2010.

Materials and methods

Data were from three waves of the Korean National Oral Health Surveys between 2003 and 2010, including a total of 23 059 children (11 889 boys and 11 170 girls) aged 8, 10, and 12 years. The impacts of sealant and water fluoridation on dental caries were obtained by logistic regression for each age group of children. The contributions of sealant and water fluoridation to the time trends in the prevalence of dental caries were examined by a series of logistic regression models, and changes in the adjusted odds ratios for each survey year were also calculated.

Results

Over the past 7 years, the prevalence of dental caries decreased dramatically. Although sealant had a significant impact on dental caries in each survey year, remarkable decreases in dental caries from 2003 to 2010 were not explained by the secular changes in the dental sealant or water fluoridation factor.

Conclusion

We observed important population declines in dental caries in Korea in children aged 8–12 years; however, the likely causes for these secular trends remain to be determined.
‘I think other parents might. …’: Using a projective technique to explore parental supply of alcohol
Authors: Jones Sandra C. , Magee Christopher , Andrews Kelly
Published: March 2015

Introduction and Aims

A growing body of research indicates parental supply of alcohol to children and adolescents is common. The present study aimed to examine parents' reasons for supplying alcohol to adolescents that they may find hard to articulate or not be consciously aware of.

Design and Methods

A projective methodology was used, whereby respondents were asked to explain the thoughts and motivations of a gender‐matched parent in a scenario in which the parent did or did not provide alcohol to their teenage child. Respondents were 97 mothers and 83 fathers of teenagers who completed an anonymous online survey. Open‐ended responses were coded thematically; t‐tests were used to compare quantitative responses between the scenarios.

Results

The quantitative analysis found the parent who provided alcohol was less likely to be seen as making sure their child was safe and educating them about boundaries, but more likely to be seen as being a friend as well as a parent and (for females only) making sure their child fits in with others. The open‐ended responses showed explanations for not providing alcohol most commonly focused on ensuring the child's safety, obeying the law, and setting rules and boundaries, and for providing alcohol focused on ensuring the child fit in with peers and beliefs about harm minimisation.

Discussion and Conclusions

The findings suggest that these respondents (parents) harboured a number of misperceptions about underage drinking and experienced conflicts in weighing up the perceived benefits of providing alcohol to their children against the risks of adolescent drinking. [Jones SC, Magee C, Andrews K. ‘I think other parents might. …’: Using a projective technique to explore parental supply of alcohol. Drug Alcohol Rev 2015;34:531–9]
Relations between infants’ emerging reach‐grasp competence and event‐related desynchronization in EEG
Authors: Cannon Erin N. , Simpson Elizabeth A. , Fox Nathan A. , Vanderwert Ross E. , Woodward Amanda L. , Ferrari Pier F.
Published: March 2015

Recent reports of similar patterns of brain electrical activity (electroencephalogram: EEG) during action execution and observation, recorded from scalp locations over motor‐related regions in infants and adults, have raised the possibility that two foundational abilities – controlling one's own intentional actions and perceiving others’ actions – may be integrally related during ontogeny. However, to our knowledge, there are no published reports of the relations between developments in motor skill (i.e. recording actual motor skill performance) and EEG during both action execution and action observation. In the present study we collected EEG from 21 9‐month‐olds who were given opportunities to reach for toys and who also observed an experimenter reach for toys. Event‐related desynchronization (ERD) was computed from the EEG during the reaching events. We assessed infants’ reaching‐grasping competence, including reach latency, errors, preshaping of the hand, and bimanual reaches, and found that desynchronization recorded in scalp electrodes over motor‐related regions during action observation was associated with action competence during execution. Infants who were more competent reachers, compared to less competent reachers, exhibited greater ERD while observing reaching‐grasping. These results provide initial evidence for an early emerging neural system integrating one's own actions with the perception of others’ actions.
When infants talk, infants listen: pre‐babbling infants prefer listening to speech with infant vocal properties
Authors: Masapollo Matthew , Polka Linda , Ménard Lucie
Published: March 2015

To learn to produce speech, infants must effectively monitor and assess their own speech output. Yet very little is known about how infants perceive speech produced by an infant, which has higher voice pitch and formant frequencies compared to adult or child speech. Here, we tested whether pre‐babbling infants (at 4–6 months) prefer listening to vowel sounds with infant vocal properties over vowel sounds with adult vocal properties. A listening preference favoring infant vowels may derive from their higher voice pitch, which has been shown to attract infant attention in infant‐directed speech (IDS). In addition, infants' nascent articulatory abilities may induce a bias favoring infant speech given that 4‐ to 6‐month‐olds are beginning to produce vowel sounds. We created infant and adult /i/ (‘ee’) vowels using a production‐based synthesizer that simulates the act of speaking in talkers at different ages and then tested infants across four experiments using a sequential preferential listening task. The findings provide the first evidence that infants preferentially attend to vowel sounds with infant voice pitch and/or formants over vowel sounds with no infant‐like vocal properties, supporting the view that infants' production abilities influence how they process infant speech. The findings with respect to voice pitch also reveal parallels between IDS and infant speech, raising new questions about the role of this speech register in infant development. Research exploring the underpinnings and impact of this perceptual bias can expand our understanding of infant language development.
Dose‐ranging efficacy and safety study of ertugliflozin, a sodium‐glucose co‐transporter 2 inhibitor, in patients with type 2 diabetes on a background of metformin
Authors: Amin N. B. , Wang X. , Jain S. M. , Lee D. S. , Nucci G. , Rusnak J. M.
Published: March 2015

Aim

To investigate the efficacy and safety of ertugliflozin, in a phase II dose‐ranging study, in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin.

Methods

A total of 328 patients [mean T2DM duration, 6.3 years; mean glycated haemoglobin (HbA1c), 8.1%] were randomized to once‐daily ertugliflozin (1, 5, 10, 25 mg), sitagliptin (100 mg) or placebo, for 12 weeks. The primary efficacy endpoint was change from baseline to week 12 in HbA1c concentration and the secondary efficacy endpoints were changes from baseline to week 12 in body weight, fasting plasma glucose (FPG) and systolic/diastolic blood pressure (SBP/DBP). Safety and tolerability were also monitored.

Results

Ertugliflozin (1–25 mg/day) produced significant reductions in HbA1c concentration [placebo‐corrected least‐squares mean (LSM) −0.45% (1 mg) to −0.72% (25 mg); p ≤ 0.002, similar to sitagliptin (−0.76%; p = 0.0001)], FPG (LSM −1.17 to −1.90 mmol/l; p < 0.0001) and body weight (−1.15 to −2.15%; p < 0.0001). The LSM SBP decreased by −3.4 to −4.0 mmHg from baseline with ertugliflozin 5–25 mg/day. No reductions in body weight or blood pressure were observed with sitagliptin. After randomization, 2.7% of patients (9/328) withdrew because of adverse events (AEs); the frequency of AEs was evenly distributed across groups. No dose‐related increase in AE frequency occurred with ertugliflozin. Hypoglycaemia was reported in 5 (1.5%) randomized participants (all in the ertugliflozin group). The frequency of urinary tract infection was 3.2% for ertugliflozin (pooled across groups), 1.8% for sitagliptin, 7.4% for placebo, and the frequency of genital fungal infections was 3.7% for ertugliflozin (pooled) versus 1.9% for placebo.

Conclusion

Ertugliflozin (1–25 mg/day) improved glycaemic control, body weight and blood pressure in patients with T2DM suboptimally controlled on metformin, and was well tolerated.
Patterns of use and outcome of inferior vena cava filters in a tertiary care setting
Authors: Rottenstreich Amihai , Spectre Galia , Roth Batia , Bloom Allan I. , Kalish Yosef
Published: March 2015

Background

Inferior vena cava (IVC) filter placement is increasing although the evidence to justify their use is limited. Many filters are left in place indefinitely, thereby exposing patients to long‐term complications.

Objectives

To review indications, complications, and follow‐up data of patients undergoing IVC filter placement at our center.

Methods

A retrospective review of consecutive admitted patients who underwent IVC filter insertion in a large university hospital with a level I trauma center. Thrombosis specialists retrospectively assessed the appropriateness of indication for IVC filter placement as well as referral for retrieval.

Results

Overall, 405 filters were inserted between 2009 and 2013. All filters were retrievable. IVC filter was placed as a primary prevention in 42% of patients. Fifty‐two patients (12.8%) experienced at least one filter‐related complication. The most common complication was deep vein thrombosis occurring in 6.9% of cases. Almost a third of all complications occurred in filters originally placed for prophylactic indications. Only 13.6% of filters were successfully removed. Nevertheless, according to our reviewers, an attempt for filter retrieval should have been made in 57% of all cases and in 86% of trauma patients. A significantly higher retrieval rate was found in patients followed at our thrombosis clinic (P < 0.01). During follow‐up, 95 patients (23.4%) died, most of them with active cancer.

Conclusions

IVC filters are placed in many cases for prophylactic indications. Their low retrieval rates together with relatively high risk of long‐term complications, questions their extensive utilization. Prospective trials addressing the safety and efficacy of IVC filters are still warranted.
Pathophysiology, diagnosis, and treatment of paroxysmal nocturnal hemoglobinuria: a review
Authors: Devalet Bérangère , Mullier François , Chatelain Bernard , Dogné Jean‐Michel , Chatelain Christian
Published: March 2015

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder of the hematopoietic stem cell that makes blood cells more sensitive to the action of complement. Patients experience intravascular hemolysis, smooth muscle dystonia, renal failure, arterial and pulmonary hypertension, recurrent infectious diseases and an increased risk of notably dreadful thrombotic complications. The diagnosis is made by flow cytometry. Efforts have been recently performed to improve the sensitivity and the standardization of this technique. PNH is frequently associated with aplastic anemia or low‐risk myelodysplasia and may be asymptomatic. Management of the classical form of PNH has been dramatically revolutionized by the development of eculizumab, which brings benefits in terms of hemolysis, quality of life, renal function, thrombotic risk, and life expectancy. Prophylaxis and treatment of arterial and venous thrombosis currently remain a challenge in PNH.
Orexin‐1 receptor signaling increases motivation for cocaine‐associated cues
Authors: Bentzley Brandon S. , Aston‐Jones Gary
Published: March 2015

The orexin/hypocretin system is involved in multiple cocaine addiction processes that involve drug‐associated environmental cues, including cue‐induced reinstatement of extinguished cocaine seeking and expression of conditioned place preference. However, the orexin system does not play a role in several behaviors that are less cue‐dependent, such as cocaine‐primed reinstatement of extinguished cocaine seeking and low‐effort cocaine self‐administration. We hypothesized that cocaine‐associated cues, but not cocaine alone, engage signaling at orexin‐1 receptors (OX1Rs), and this cue‐engaged OX1R signaling increases motivation for cocaine. Motivation for cocaine was measured in Sprague–Dawley rats with behavioral‐economic demand curve analysis after pretreatment with the OX1R antagonist SB‐334867 (SB) or vehicle with and without light + tone cues. Demand for cocaine was higher when cocaine‐associated cues were present, and SB only reduced cocaine demand in the presence of these cues. We then investigated whether cocaine demand was linked to the cued reinstatement of cocaine seeking, as both procedures are partially driven by cocaine‐associated cues in an orexin‐dependent manner. SB blocked cue‐induced reinstatement behavior, and baseline demand predicted SB efficacy with the largest effect in high‐demand animals, i.e. animals with the greatest cue‐dependent behavior. We conclude that OX1R signaling increases the reinforcing efficacy of cocaine‐associated cues but not that of cocaine alone. This supports our view that orexin plays a prominent role in the ability of conditioned cues to activate motivational responses.