bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrated semi‐physiological pharmacokinetic model for both sunitinib and its active metabolite SU12662
Authors: Yu Huixin , Steeghs Neeltje , Kloth Jacqueline S. L. , de Wit Djoeke , van Hasselt J. G. Coen , van Erp Nielka P. , Beijnen Jos H. , Schellens Jan H. M. , Mathijssen Ron H. J. , Huitema Alwin D. R.
Published: November 2014

Aims

Previously published pharmacokinetic (PK) models for sunitinib and its active metabolite SU12662 were based on a limited dataset or lacked important elements such as correlations between sunitinib and its metabolite. The current study aimed to develop an improved PK model that circumvented these limitations and to prove the utility of the PK model in treatment optimization in clinical practice.

Methods

One thousand two hundred and five plasma samples from 70 cancer patients were collected from three PK studies with sunitinib and SU12662. A semi‐physiological PK model for sunitinib and SU12662 was developed incorporating pre‐systemic metabolism using non‐linear mixed effects modelling (nonmem). Allometric scaling based on body weight was applied. The final model was used for simulation of the PK of different treatment regimens.

Results

Sunitinib and SU12662 PK were best described by a one and two compartment model, respectively. Introduction of pre‐systemic formation of SU12662 strongly improved model fit, compared with solely systemic metabolism. The clearance of sunitinib and SU12662 was estimated at 35.7 (relative standard error (RSE) 5.7%) l h−1 and 17.1 (RSE 7.4%) l h−1, respectively for 70 kg patients. Correlation coefficients were estimated between inter‐individual variability of both clearances, both volumes of distribution and between clearance and volume of distribution of SU12662 as 0.53, 0.48 and 0.45, respectively. Simulation of the PK model predicted correctly the ratio of patients who did not reach proposed PK targets for efficacy.

Conclusions

A semi‐physiological PK model for sunitinib and SU12662 in cancer patients was presented including pre‐systemic metabolism. The model was superior to previous PK models in many aspects.
A population model of early rheumatoid arthritis disease activity during treatment with methotrexate, sulfasalazine and hydroxychloroquine
Authors: Wojciechowski Jessica , Wiese Michael D. , Proudman Susanna M. , Foster David J. R. , Upton Richard N.
Published: November 2014

Aims

To develop a population model describing the disease activity (DAS28) time course in patients with early rheumatoid arthritis (RA) treated with triple disease‐modifying anti‐rheumatic drug (DMARD) therapy (methotrexate, sulfasalazine and hydroxychloroquine).

Methods

DAS28 was obtained in 263 patients with early RA from initiation of therapy until 60 weeks. Using nonmem®, base models (DAS28 vs. time) and covariate influences were investigated for the population.

Results

The best model was an exponential model of DAS28 vs. time that was additive to baseline DAS28, with covariance between parameters, and a combined residual error model. Age and patient smoking history were covariates significantly affecting response to therapy. Population estimates were baseline DAS28 (5.7), extent of change in DAS28 (−2.8) and the half‐life of disease activity (6.2 weeks; time to steady disease state achieved within approximately 30 weeks). Older individuals exhibited more severe baseline DAS28, described by a power function centred around 57 years (baseline DAS28 for 40‐ and 70‐year‐old patients were 5.4 vs. 5.8, respectively) and current smokers took longer to achieve a steady disease state (approximately 50 weeks). There was considerable within‐patient random variability in DAS28 over time (empirical 90% CI for DAS28 in a population typical patient at 60 weeks: 1.8, 4.2 with median value of 2.8).

Conclusions

This is the first report of a disease activity model for early RA treated with triple DMARD therapy. Smoking and age were identified as covariates.
Identification of muscarinic receptor subtypes involved in catecholamine secretion in adrenal medullary chromaffin cells by genetic deletion
Authors: Harada Keita , Matsuoka Hidetada , Miyata Hironori , Matsui Minoru , Inoue Masumi
Published: November 2014

Background and Purpose

Activation of muscarinic receptors results in catecholamine secretion in adrenal chromaffin cells in many mammals, and muscarinic receptors partly mediate synaptic transmission from the splanchnic nerve, at least in guinea pigs. To elucidate the physiological functions of muscarinic receptors in chromaffin cells, it is necessary to identify the muscarinic receptor subtypes involved in excitation.

Experimental Approach

To identify muscarinic receptors, pharmacological tools and strains of mice where one or several muscarinic receptor subtypes were genetically deleted were used. Cellular responses to muscarinic stimulation in isolated chromaffin cells were studied with the patch clamp technique and amperometry.

Key Results

Muscarinic M1, M4 and M5 receptors were immunologically detected in mouse chromaffin cells, and these receptors disappeared after the appropriate gene deletion. Mouse cells secreted catecholamines in response to muscarinic agonists, angiotensin II and a decrease in external pH. Genetic deletion of M1, but not M3, M4 or M5, receptors in mice abolished secretion in response to muscarine, but not to other stimuli. The muscarine‐induced secretion was suppressed by MT7, a snake peptide toxin specific for M1 receptors. Similarly, muscarine failed to induce an inward current in the presence of MT7 in mouse and rat chromaffin cells. The binding affinity of VU0255035 for the inhibition of muscarine‐induced currents agreed with that for the M1 receptor.

Conclusions and Implications

Based upon the effects of genetic deletion of muscarinic receptors and MT7, it is concluded that the M1 receptor alone is responsible for muscarine‐induced catecholamine secretion.
Antibiotic Adjuvants: Diverse Strategies for Controlling Drug‐Resistant Pathogens
Authors: Gill Erin E. , Franco Octavio L. , Hancock Robert. E. W.
Published: November 2014

The growing number of bacterial pathogens that are resistant to numerous antibiotics is a cause for concern around the globe. There have been no new broad‐spectrum antibiotics developed in the last 40 years, and the drugs we have currently are quickly becoming ineffective. In this article, we explore a range of therapeutic strategies that could be employed in conjunction with antibiotics and may help to prolong the life span of these life‐saving drugs. Discussed topics include antiresistance drugs, which are administered to potentiate the effects of current antimicrobials in bacteria where they are no longer (or never were) effective; antivirulence drugs, which are directed against bacterial virulence factors; host‐directed therapies, which modulate the host's immune system to facilitate infection clearance; and alternative treatments, which include such therapies as oral rehydration for diarrhea, phage therapy, and probiotics. All of these avenues show promise for the treatment of bacterial infections and should be further investigated to explore their full potential in the face of a postantibiotic era.
A low postoperative nonstimulated serum thyroglobulin level excludes the presence of persistent disease in low‐risk papillary thyroid cancer patients: implication for radioiodine indication
Authors: Rosario Pedro W. , Mourão Gabriela F. , Siman Thassio Leonardo , Calsolari Maria Regina
Published: November 2014

Objective

To evaluate the presence of persistent disease, including on post‐therapy whole‐body scan (RxWBS), in low‐risk patients with papillary thyroid carcinoma (PTC) >1 cm who have low nonstimulated thyroglobulin (Tg) (measured with a sensitive assay), negative anti‐Tg antibodies (TgAb) and neck ultrasound (US) showing no metastases after total thyroidectomy.

Patients

We studied 154 patients with PTC >1 cm classified as low risk, who had US without metastases, negative TgAb, nonstimulated Tg ≤ 0·25 ng/ml and TSH ≤2 mIU/l about 3 months after total thyroidectomy.

Results

Tg measured immediately before 131I was ≤1 ng/ml in 89·5% of the patients and >1 ng/ml in 10·5%. None of the patients showed ectopic uptake on RxWBS. Uptake in the thyroid bed was observed in 146 (94·8%) patients and was ≤2% in all of them. In the control assessment 9–12 months after ablation, stimulated Tg (sTg) ≤1 ng/ml was achieved in 150 patients (97·4%). Only one patient had sTg >2 ng/ml (2·5 ng/ml) and none of the patients had apparent disease detected by imaging methods. During further short‐term follow‐up after control assessment (median of 24 months), none of the patients had tumour recurrence.

Conclusions

The combination of nonstimulated Tg ≤0·25 ng/ml, negative TgAb and US without metastases after thyroidectomy rules out the presence of persistent disease (including on RxWBS) in low‐risk patients with PTC >1 cm. This demonstration weakens the indication of ablation with 131I in these cases.
The Rockefeller University Graduate Tracking Survey System
Authors: Romanick Michelle , Ng Kwan , Lee George , Herbert Matthew , Coller Barry S.
Published: November 2014

Background

It is essential to track the careers and accomplishments of the graduates of translational research training programs to assess the impact of the programs and to improve them. The major obstacle is the lack of a convenient method to collect the information in a comprehensive and standardized manner.

Methods

We have developed a Web‐based electronic Graduate Tracking Survey System (GTSS) that prepopulates the graduate's information on publications, grants, patents, and clinical trials from public data sources, thus insuring a uniform data format, facilitating survey completion, and facilitating the aggregation of data at individual or multiple sites. GTSS questions are designed to assess whether trainees make important contributions that improve human health, and to track related “surrogate” career development indicators of likely future success.

Results

The GTSS has been in use at Rockefeller University since 2011 and has been adopted by 21 other Clinical and Translational Science Award programs.

Conclusions

The GTSS provides an efficient and convenient mechanism to track the graduates of a wide variety of training programs. It has the potential to aggregate standardized data across institutions, thus providing benchmarks for the assessment of individual training programs and data for program improvement.
Diagnostic and therapeutic utility of SpyGlass® peroral cholangioscopy in intraductal biliary disease: Single‐center, retrospective, cohort study
Authors: Tieu Alan H. , Kumbhari Vivek , Jakhete Neha , Onyimba Frances , Patel Yuval , Shin Eun Ji , Li Zhiping
Published: November 2014

Background and Aim

SpyGlass® cholangiopancreatoscopy system has shown early success in aiding diagnosis and management of pancreaticobiliary diseases. We aimed to assess the technical success, clinical success, diagnostic yield, therapeutic yield, and safety of the SpyGlass® system at a single institution.

Methods

A retrospective, single‐center review of consecutive patients who underwent endoscopic retrograde cholangiopancreatography with SpyGlass® between January 2008 and August 2013 for a variety of indications. Technical success was defined as the procedure being completed as planned. Clinical success was defined as a successful outcome using diagnostic, clinical, laboratory, or imaging evidence.

Results

SpyGlass® cholangioscopy was carried out in 88 patients (49 females, mean age 56.9 ± 15.5 years). Indications were diagnostic in 67 and therapeutic in 21. Overall, technical success was seen in 87.5% and clinical success in 77.3%. Thirty‐nine patients with indeterminate biliary stricture had technical and clinical success rates of 92.3% and 74.4%, respectively. In this subgroup, malignancy was ultimately diagnosed in 13 with 12 patients diagnosed by SpyGlass® and confirmed by surgical specimens in 12/12 cases; positive predictive value 100%). In the 23 remaining patients with indeterminate biliary strictures, one was later found to have malignancy (negative predictive value 95.8%) after 1 year of follow up. In the 13 therapeutic cases of stone removal, technical and clinical success was seen in 77.0% for both. Overall, adverse events were seen in 15.9%.

Conclusions

SpyGlass® demonstrated acceptable technical and clinical success rates in both diagnostic and therapeutic procedures. In particular, it allows for an accurate rate of diagnosis of indeterminate biliary strictures.
BUYING THEIR VOTES? A STUDY OF LOCAL TAX‐PRICE DISCRIMINATION
Authors: Reback Randall
Published: November 2014

A population's demographic composition may affect political support for various public services. This article examines whether the aging‐in‐place of local residents decreases financial support for public schools in the United States. I expand on previous empirical work by examining whether tax‐price reductions offered to elderly homeowners moderate their effect on local school revenues. The results reveal that an aging population structure substantially decreases school revenues, unless elderly homeowners receive state‐financed reductions in their local tax‐prices. Sizable differences hold even when comparing school districts located near each other but on opposite sides of state borders. Given the imminent aging of the population structure in the United States and many other developed countries, governments' targeted tax reduction policies could have important effects on equilibrium school revenues. (JEL I22, J14, H71)
Evaluation of a digital learning object (DLO) to support the learning process in radiographic dental diagnosis
Authors: Busanello F. H. , da Silveira P. F. , Liedke G. S. , Arús N. A. , Vizzotto M. B. , Silveira H. E. D. , Silveira H. L. D.
Published: November 2014

Aims

Studies have shown that inappropriate therapeutic strategies may be adopted if crown and root changes are misdiagnosed, potentially leading to undesirable consequences. Therefore, the aim of this study was to evaluate a digital learning object, developed to improve skills in diagnosing radiographic dental changes.

Materials and Methods

The object was developed using the Visual Basic Application (VBA) software and evaluated by 62 undergraduate students (male: 24 and female: 38) taking an imaging diagnosis course. Participants were divided in two groups: test group, which used the object and control group, which attended conventional classes. After 3 weeks, students answered a 10‐question test and took a practice test to diagnose 20 changes in periapical radiographs.

Results

The results show that test group performed better that control group in both tests, with statistically significant difference (P = 0.004 and 0.003, respectively). In overall, female students were better than male students. Specific aspects of object usability were assessed using a structured questionnaire based on the System Usability Scale (SUS), with a score of 90.5 and 81.6 by male and female students, respectively.

Conclusions

The results obtained in this study suggest that students who used the DLO performed better than those who used conventional methods. This suggests that the DLO may be a useful teaching tool for dentistry undergraduates, on distance learning courses and as a complementary tool in face‐to‐face teaching.
Nonlinear elastic–plastic stress investigation for two interacting 3‐D cracks in offshore pipelines
Authors: Zhang Y. M. , Ariffin M. Z. , Xiao Z. M. , Zhang W. G. , Huang Z. H.
Published: November 2014

Under continuous loading conditions, small closely distanced cracks can grow and coalesce into a large one that may subsequently pose a threat to the integrity and safety of structures. Although many research works were carried out for predicting fatigue growth of multiple cracks, few papers focusing on nonlinear elastic–plastic analysis of multiple cracks' fracture behaviours can be referred to. In this study, 3‐D elastic–plastic investigation has been performed on fracture behaviours of two collinear cracks located in offshore pipelines. The influences of the cracks configuration, the separation distance and internal pressure of the pipeline on the crack behaviours are investigated. On the basis of the numerical results, a new strain‐based crack tip opening displacement estimation method is proposed for assessing the fracture behaviour of flawed pipelines with two interacting collinear cracks.
Hydrocarbons preserved in a ~2.7 Ga outcrop sample from the Fortescue Group, Pilbara Craton, Western Australia
Authors: Hoshino Y. , Flannery D. T. , Walter M. R. , George S. C.
Published: November 2014

The hydrocarbons preserved in an Archean rock were extracted, and their composition and distribution in consecutive slices from the outside to the inside of the rock were examined. The 2.7 Ga rock was collected from the Fortescue Group in the Pilbara region, Western Australia. The bitumen I (solvent‐extracted rock) and bitumen II (solvent‐extracted hydrochloric acid‐treated rock) fractions have different hydrocarbon compositions. Bitumen I contains only trace amounts of aliphatic hydrocarbons and virtually no aromatic hydrocarbons. In contrast, bitumen II contains abundant aliphatic and aromatic hydrocarbons. The difference seems to reflect the weathering history and preservational environment of the investigated rock. Aliphatic hydrocarbons in bitumen I are considered to be mainly from later hydrocarbon inputs, after initial deposition and burial, and are therefore not indigenous. The lack of aromatic hydrocarbons in bitumen I suggests a severe weathering environment since uplift and exposure of the rock at the Earth's surface in the Cenozoic. On the other hand, the high abundance of aromatic hydrocarbons in bitumen II suggests that bitumen II hydrocarbons have been physically isolated from removal by their encapsulation within carbonate minerals. The richness of aromatic hydrocarbons and the relative scarcity of aliphatic hydrocarbons may reflect the original compositions of organic materials biosynthesised in ancient organisms in the Archean era, or the high thermal maturity of the rock. Cyanobacterial biomarkers were observed in the surficial slices of the rock, which may indicate that endolithic cyanobacteria inhabited the surface outcrop. The distribution of aliphatic and aromatic hydrocarbons implies a high thermal maturity, which is consistent with the lack of any specific biomarkers, such as hopanes and steranes, and the prehnite–pumpellyite facies metamorphic grade.
Inflammatory pseudotumours of the oesophagus – histological and immunohistochemical findings
Authors: Sy Keiyan , Parfitt Jeremy , Marginean Celia , Riddell Robert H , Streutker Catherine J
Published: November 2014

Aims

Inflammatory oesophageal pseudotumours are rare lesions, thought to be reactive. Due to marked atypia of the stromal cells, these can be misdiagnosed as malignancies. The objective of this study was to characterize histological and immunohistochemical features of a series of inflammatory pseudotumours of the oesophagus.

Methods and results

We present 12 cases of inflammatory oesophageal pseudotumours, occurring in seven females and five males, with a mean age of 57.3 years. Clinical presentations were variable; dysphagia, abdominal pain and weight loss and upper gastrointestinal bleed. In a majority of the cases, nodules or masses in the distal oesophagus were identified at endoscopy. Microscopically, the lamina propria in all 12 cases contained inflammation and granulation tissue. Ten of 12 cases showed mucosal ulceration and 11 of 12 cases had acutely inflamed epithelium. Markedly atypical pleomorphic stromal cells with prominent nucleoli were identified in all 12 cases. Immunohistochemistry showed uniform positivity for vimentin in 11 of 11 cases, and two of seven cases demonstrated weak focal positivity for smooth muscle actin. The cells were negative for all other markers.

Conclusions

Reactive oesophageal lesions can show marked nuclear atypia in stromal fibroblasts/myofibroblasts, which are easily mistaken for malignancies. Pathologists must consider the diagnosis of an inflammatory pseudotumour if stromal atypia is present in an inflammatory background.
Applying micro-costing methods to estimate the costs of pharmacy interventions: an illustration using multi-professional clinical medication reviews in care homes for older people
Authors: Sach Tracey H , Desborough James , Houghton Julie , Holland Richard
Published: November 2014

Objectives

Economic methods are underutilised within pharmacy research resulting in a lack of quality evidence to support funding decisions for pharmacy interventions. The aim of this study is to illustrate the methods of micro-costing within the pharmacy context in order to raise awareness and use of this approach in pharmacy research.

Methods

Micro-costing methods are particularly useful where a new service or intervention is being evaluated and for which no previous estimates of the costs of providing the service exist. This paper describes the rationale for undertaking a micro-costing study before detailing and illustrating the process involved. The illustration relates to a recently completed trial of multi-professional medication reviews as an intervention provided in care homes. All costs are presented in UK£2012.

Key findings

In general, costing methods involve three broad steps (identification, measurement and valuation); when using micro-costing, closer attention to detail is required within all three stages of this process. The mean (standard deviation; 95% confidence interval (CI) ) cost per resident of the multi-professional medication review intervention was £104.80 (50.91; 98.72 to 109.45), such that the overall cost of providing the intervention to all intervention home residents was £36,221.29 (95% CI, 32 810.81 to 39 631.77).

Conclusions

This study has demonstrated that micro-costing can be a useful method, not only for estimating the cost of a pharmacy intervention to feed into a pharmacy economic evaluation, but also as a source of information to help inform those designing pharmacy services about the potential time and costs involved in delivering such services.
The use of polyunsaturated fatty acids in ocular hypertension.: A study with blue‐on‐yellow perimetry
Authors: Cellini M. , Rossi A. , Moretti M.
Published: November 2014

The authors have evaluated the efficacy of systemic treatment with omega‐3 polyunsaturated fatty acids in improving the blue/yellow perimetric indices in patients suffering from ocular hypertension.

A total of 40 such patients with mean IOP 22.4±2.6 mmHg, who showed pathological values of mean defect (MD) and the correct pattern standard deviation (CPSD) with blue/yellow perimetry, were treated. Omega‐3 polyunsaturated fatty acids were administered in high doses to them. After three months of therapy, significant improvements in both MD (from —4.845 ± 2.571 dB to —3.720 ± 2.324 dB (p<0.001) and CPSD (from 3.115 ± 1.647 db to 2.860 ± 1.518 dB (p<0.023) were seen in the treated group.

Polyunsaturated fatty acids must be considered an efficacious supportive therapy in the prevention and treatment of glaucomatous optic neuropathy.
Deep sclerectomy in glaucoma. Preliminary results
Authors: Brusini Paolo , Tosoni Claudia
Published: November 2014

The authors report the main intra‐operational problems and difficulties they have found with deep sclerectomy, a new surgical procedure for glaucoma. The early post‐operational complications and the short‐term results are also reported. Deep sclerectomy appears to be a safe and effective procedure in various types of glaucoma patients, but randomized prospective long‐term studies are needed to declare that classical trabeculectomy is out‐moded.
The Ibopamine provocative test in patients with diagnosis of open‐angle glaucoma: a ten‐year follow‐up
Authors: Giraldi J. Pecori , Santerelli S. , Di Tizio F. , Saguto D. , Cordiani B. , Zaccara F. , Paone E.
Published: November 2014

The results obtained in a ten‐year follow‐up of 32 patients with diagnosis of open‐angle glaucoma in which the ibopamine provocative test was repeated at least three times at regular intervals are reported. The positivity of the test proved to be maintained constant through time, thus confirming its high specificity in revealing compromission of aqueous humour outflow pathways.
Compliance and psychological conditions: a long‐term investigation in 245 glaucomatous patients
Authors: Giraldi J. Pecori , Liguori A. , Mollicone A. , Paone E.
Published: November 2014

A long‐term epidemiological investigation was made with 245 open‐angle glaucoma patients classed in 3 age bands and by sex, with the aim of determining the prevalence of compliance and the psychological conditions induced by the extended time factor of the disease.

It became clear that a good level of compliance can be obtained if patients understand the severity of the disease and its possible consequences and a good relationship exists between patient and doctor.

The higher tendency towards depression in under‐45‐year‐old women is, perhaps, due to the undesirability of having to accept a situation requiring an indefinite period of treatment.
Compensation for Historical Emissions and Excusable Ignorance
Authors: Zellentin Alexa
Published: November 2014

This article defends the idea of applying principles of corrective justice to the matter of climate change. In particular, it argues against the excusable ignorance objection, which holds that historical emissions produced at a time when our knowledge of climate change was insufficient ought to be removed from the equation when applying rectificatory principles to this context. In constructing my argument, I rely on a particular interpretation of rectificatory justice and outcome responsibility. I also address the individualism objection by showing why we should view states as relevant agents of climate change. This argument is built on the assumption that states are institutions set up to coordinate and regulate human interaction, so as to protect their citizens from the unwanted consequences of such interaction.
Conditional Deliberation: The Case of Joint Parliamentary Committees in theEU
Authors: Ozcurumez Saime , Hoxha Julinda
Published: November 2014

Deliberation, as a mode of interaction based on the logic of reason‐giving argumentation, is a core feature of theEuropeanUnion institutions. Yet only few studies have explored the conditions that make deliberation possible in practice. This study examines the institutional determinants of deliberation within joint parliamentary committees (JPCs) – longstanding instruments ofEUenlargement policy. The empirical analysis reveals a dynamic relationship between ‘deliberation’ and ‘debate’ as extreme modes of interaction that co‐exist within the same setting. It also suggests that deliberation is a product of participants' constant efforts to maintain equal power relations and low issue‐area sensitivity. This study provides new evidence on deliberative politics at theEUlevel. In addition, it highlights the role of inter‐parliamentary deliberation as a catalyst for political co‐operation and policy co‐ordination, at a time of intensifying enlargement fatigue and growingEuroscepticism both at home and abroad.
Overdominance interacts with linkage to determine the rate of adaptation to a new optimum
Authors: Draghi J. , Whitlock M. C.
Published: November 2014

Overdominance, or a fitness advantage of a heterozygote over both homozygotes, can occur commonly with adaptation to a new optimum phenotype. We model how such overdominant polymorphisms can reduce the evolvability of diploid populations, uncovering a novel form of epistatic constraint on adaptation. The fitness load caused by overdominant polymorphisms can most readily be ameliorated by evolution at tightly linked loci; therefore, traits controlled by multiple loosely linked loci are predicted to be strongly constrained. The degree of constraint is also sensitive to the shape of the relationship between phenotype and fitness, and the constraint caused by overdominance can be strong enough to overcome the effects of clonal interference on the rate of adaptation for a trait. These results point to novel influences on evolvability that are specific to diploids and interact with genetic architecture, and they predict a source of stochastic variability in eukaryotic evolution experiments or cases of rapid evolution in nature.
A method for prioritizing interventions following root cause analysis (RCA): lessons from philosophy
Authors: Boyd Matt
Published: November 2014

Rationale, aims and objectives

Root cause analysis (RCA) is widely used to investigate adverse events in health care and is mandated by many organizations and governments. RCA employs a combination of techniques to establish the factors contributing to a harmful outcome. Once the factors are identified, then interventions are usually designed in order to prevent further harms from occurring. Prior to deciding which intervention(s) to implement, we must make judgements of causal importance in the context of multiple, interacting conditions. Clearly, we must take action to prevent adverse events, but we need not take action against every contributing cause. I aim to show that many causal factors can be identified by RCA, but current approaches do not adequately distinguish among these causes, leaving numerous potential targets of intervention. I argue that this is because the literature on RCA (with few exceptions) has largely neglected the literature on philosophy of causation and explanation.

Method

In this paper, I focus on demonstrating how Strevens' kairetic approach to explanation and Tinbergen's four questions to explain behaviour have the potential to work synergistically with the present RCA methods.

Result

There are important lessons we can bring to RCA from the literature on causation and explanation, particularly from the philosophy of science and biology.

Conclusion

This work could enhance the effectiveness of RCA by identifying and understanding the causes that really make a difference to adverse events. This ought to reduce the number of targets and focus intervention following RCA.
Variations in lipid screening frequency in family medicine patients with cardiovascular risk factors
Authors: Doganer Yusuf C. , Rohrer James E. , Angstman Kurt B. , Merry Stephen P. , Erickson Jacob L.
Published: November 2014

Rationale, aims and objectives

This study was undertaken to assess the frequency of lipid screening in comparison with the United States Preventive Services Task Force guideline in a sample of family medicine patients. In addition, we sought to determine the association between testing frequency and achievement of lipid targets.

Methods

A random sample was extracted from 271 patients from among all patients cared for in our Department of Family Medicine for whom lipid screening was ordered from March to September 2012 and who had ≥2 well‐defined cardiovascular risk factors. Lipid testing frequency was classified in three ways: semi‐annual or less often (0–12 tests over 6 years), annual or less often (0–6 tests), or biennial (0–3 tests).

Results

Multiple logistic regression analysis revealed that the predictors of lipid screening more often than semi‐annually were age ≥60 years [odds ratio (OR) = 3.7] and diabetes mellitus (DM) (OR = 30.6). Predictors of screening more often than annually were DM (OR = 4.3), hypertension (OR = 2.1), family history of premature coronary artery disease (OR = 5.6) and statin treatment (OR = 3.5). Lipid goal attainment was not associated with testing frequency except with regard to low‐density lipoprotein levels (P = 0.043, P < 0.001, P = 0.005, by semi‐annual, annual and biennial, respectively) and total cholesterol levels (P = 0.015, P = 0.025 by semi‐annual and annual, respectively).

Conclusions

Questionable high frequency of lipid testing was detected even when the more conservative approach of annual monitoring was assumed. Frequency of testing was not associated with goal attainment for most parameters. Physicians should request the lipid testing based on overall risk assessment and person variability in accordance with published guidelines.
Retracted: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs‐mediated neuroinflammation in bone cancer rats
Authors: Hu Xue‐Ming , Liu Yan‐Nan , Zhang Hai‐Long , Cao Shou‐Bin , Zhang Ting , Chen Li‐Ping , Shen Wen
Published: November 2014

The activation of MAPK pathways in spinal cord and subsequent production of proinflammatory cytokines in glial cells contribute to the development of spinal central sensitization, the basic mechanism underlying bone cancer pain (BCP). Our previous study showed that spinal CXCL12 from astrocytes mediates BCP generation by binding to CXCR4 in both astrocyters and microglia. Here, we verified that CXCL12/CXCR4 signaling contributed to BCP through a MAPK‐mediated mechanism. In naïve rats, a single intrathecal administration of CXCL12 considerably induced pain hyperalgesia and phosphorylation expression of spinal MAPK members (including extracellular signal‐regulated kinase, p38, and c‐Jun N‐terminal kinase), which could be partially prevented by pre‐treatment with CXCR4 inhibitor AMD3100. This CXCL12‐induced hyperalgesia was also reduced by MAPK inhibitors. In bone cancer rats, tumor cell inoculation into the tibial cavity caused prominent and persistent pain hyperalgesia, and associated with up‐regulation of CXCL12 and CXCR4, activation of glial cells, phosphorylation of MAPKs, and production of proinflammatory cytokines in the spinal cord. These tumor cell inoculation‐induced behavioral and neurochemical alterations were all suppressed by blocking CXCL12/CXCR4 signaling or MAPK pathways. Taken together, these results demonstrate that spinal MAPK pathways mediated CXCL12/CXCR4‐induced pain hypersensitivity in bone cancer rats, which could be druggable targets for alleviating BCP and glia‐derived neuroinflammation.

image

Following tumor cell inoculation, chemokine CXCL12 from astrocytes spreads around the spinal environment, resulting in functional activation of CXCR4‐expressing astrocytes and microglia. Once glia are activated, they may initiate MAPK (mitogen‐activated protein kinase) pathways, and subsequently produce proinflammatory cytokines and chemokines. Among them, CXCL12 could reinforce the astrocytic and microglial activation in autocrine and paracrine manners. Such positive feedback loops sustain perseverant neuroinflammation, facilitate glial activation, and finally lead to bone cancer pain. IL = interleukin; TNF = tumor necrosis factor.
S‐allyl cysteine activates the Nrf2‐dependent antioxidant response and protects neurons against ischemic injury in vitro and in vivo
Authors: Shi Huanying , Jing Xu , Wei Xinbing , Perez Ruth G. , Ren Manru , Zhang Xiumei , Lou Haiyan
Published: November 2014

Stroke is a devastating clinical condition for which an effective neuroprotective treatment is currently unavailable. S‐allyl cysteine (SAC), the most abundant organosulfur compound in aged garlic extract, has been reported to possess neuroprotective effects against stroke. However, the mechanisms underlying its beneficial effects remain poorly defined. The present study tests the hypothesis that SAC attenuates ischemic neuronal injury by activating the nuclear factor erythroid‐2‐related factor 2 (Nrf2)‐dependent antioxidant response in both in vitro and in vivo models. Our findings demonstrate that SAC treatment resulted in an increase in Nrf2 protein levels and subsequent activation of antioxidant response element pathway genes in primary cultured neurons and mice. Exposure of primary neurons to SAC provided protection against oxygen and glucose deprivation‐induced oxidative insults. In wild‐type (Nrf2+/+) mice, systemic administration of SAC attenuated middle cerebral artery occlusion‐induced ischemic damage, a protective effect not observed in Nrf2 knockout (Nrf2−/−) mice. Taken together, these findings provide the first evidence that activation of the Nrf2 antioxidant response by SAC is strongly associated with its neuroprotective effects against experimental stroke and suggest that targeting the Nrf2 pathway may provide therapeutic benefit for the treatment of stroke.

image

The transcription factor Nrf2 is involved in cerebral ischemic disease and may be a promising target for the treatment of stroke. We provide novel evidence that SAC confers neuroprotection against ischemic stroke by activating the antioxidant Nrf2 signaling pathway. ARE, antioxidant response element; GCLC, glutathione cysteine ligase regulatory subunit; GCLM, glutathione cysteine ligase modulatory subunit; HO‐1, heme oxygenase‐1; JNK, c‐Jun N‐terminal kinase; Keap1, Kelch‐like ECH‐associated protein 1; Maf, musculoaponeurotic fibrosarcoma; Nrf2, nuclear factor erythroid‐2‐related factor 2; SAC, S‐allyl cysteine; ROS, reactive oxygen species.
Pre‐synaptic C‐terminal truncated tau is released from cortical synapses in Alzheimer's disease
Authors: Sokolow Sophie , Henkins Kristen M. , Bilousova Tina , Gonzalez Bianca , Vinters Harry V. , Miller Carol A. , Cornwell Lindsey , Poon Wayne W. , Gylys Karen H.
Published: November 2014

The microtubule‐associated protein tau has primarily been associated with axonal location and function; however, recent work shows tau release from neurons and suggests an important role for tau in synaptic plasticity. In our study, we measured synaptic levels of total tau using synaptosomes prepared from cryopreserved human postmortem Alzheimer's disease (AD) and control samples. Flow cytometry data show that a majority of synaptic terminals are highly immunolabeled with the total tau antibody (HT7) in both AD and control samples. Immunoblots of synaptosomal fractions reveal increases in a 20 kDa tau fragment and in tau dimers in AD synapses, and terminal‐specific antibodies show that in many synaptosome samples tau lacks a C‐terminus. Flow cytometry experiments to quantify the extent of C‐terminal truncation reveal that only 15–25% of synaptosomes are positive for intact C‐terminal tau. Potassium‐induced depolarization demonstrates release of tau and tau fragments from pre‐synaptic terminals, with increased release from AD compared to control samples. This study indicates that tau is normally highly localized to synaptic terminals in cortex where it is well‐positioned to affect synaptic plasticity. Tau cleavage may facilitate tau aggregation as well as tau secretion and propagation of tau pathology from the pre‐synaptic compartment in AD.

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Results demonstrate the abundance of tau, mainly C‐terminal truncated tau, in synaptic terminals in aged control and in Alzheimer's disease (AD) samples. Tau fragments and dimers/oligomers are prominent in AD synapses. Following depolarization, tau release is potentiated in AD nerve terminals compared to aged controls. We hypothesize (i) endosomal release of the different tau peptides from AD synapses, and (ii) together with phosphorylation, fragmentation of synaptic tau exacerbates tau aggregation, synaptic dysfunction, and the spread of tau pathology in AD. Aβ = amyloid‐beta.
Fluctuations in nucleus accumbens extracellular glutamate and glucose during motivated glucose‐drinking behavior: dissecting the neurochemistry of reward
Authors: Wakabayashi Ken T. , Myal Stephanie E. , Kiyatkin Eugene A.
Published: November 2014

While motivated behavior involves multiple neurochemical systems, few studies have focused on the role of glutamate, the brain's excitatory neurotransmitter, and glucose, the energetic substrate of neural activity in reward‐related neural processes. Here, we used high‐speed amperometry with enzyme‐based substrate‐sensitive and control, enzyme‐free biosensors to examine second‐scale fluctuations in the extracellular levels of these substances in the nucleus accumbens shell during glucose‐drinking behavior in trained rats. Glutamate rose rapidly after the presentation of a glucose‐containing cup and before the initiation of drinking (reward seeking), decreased more slowly to levels below baseline during consumption (sensory reward), and returned to baseline when the ingested glucose reached the brain (metabolic reward). When water was substituted for glucose, glutamate rapidly increased with cup presentation and in contrast to glucose drinking, increased above baseline after rats tasted the water and refused to drink further. Therefore, extracellular glutamate show distinct changes associated with key events of motivated drinking behavior and opposite dynamics during sensory and metabolic components of reward. In contrast to glutamate, glucose increased at each stimulus and behavioral event, showing a sustained elevation during the entire behavior and a robust post‐ingestion rise that correlated with the gradual return of glutamate levels to their baseline. By comparing active drinking with passive intra‐gastric glucose delivery, we revealed that fluctuations in extracellular glucose are highly dynamic, reflecting a balance between rapid delivery because of neural activity, intense metabolism, and the influence of ingested glucose reaching the brain.

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By using enzyme‐based biosensors coupled with high‐speed amperometry, we examined the pattern of dynamic fluctuations in extracellular levels of glutamate and glucose in the nucleus accumbens during glucose‐drinking behavior in trained rats. These fluctuations are considered with respect to their functional significance in motivated behavior and their relation to sensory and metabolic aspects of reward.
Improvement of communication and interpersonal competence in telenursing – development of a self‐assessment tool
Authors: Johnson Christina , Wilhelmsson Susan , Börjeson Sussanne , Lindberg Malou
Published: November 2014

Aims and objectives

The aim of this study was to develop a self‐assessment tool aiming to raise telenurses' awareness of their communication and interpersonal competence, and highlight areas in need of improvement.

Background

Several studies have revealed the need for development of communication competence in telenursing. Structured analyses of conversations with patients/callers, is one way to increase telenurses' awareness of their unique communication and interpersonal competence.

Design

Instrument development, Validation assessment using the method Content Validity Index.

Method

The process to determine content validity was done in two stages; the development stage and the assessment stage. The development stage started with a literature search. The assessment stage was separated into two phases, assessment by an expert group and assessment and test by telenurses. The telenurses also participated in consensus discussions.

Results

A telenursing self‐assessment tool with 58 items was developed. The items were sorted into five sections according to the nursing process.

Conclusion

This study describes the thorough development process of the telenursing self‐assessment tool to be used by telenurses in order to become aware of their unique communication and interpersonal competence when analysing their own conversations with patients/callers. As a formative tool it is meant to provide self‐direction, feedback and coaching, and create learning opportunities.

Relevance to clinical practice

The self‐assessment tool helps the telenurse to follow the nursing process, to be patient‐centred, and it is meant to provide self‐direction, feedback, and coaching, as well as create learning opportunities. The tool can contribute to the development of communication and interpersonal competence in telephone advice nursing. Further development of the tool may provide an objective scoring instrument for evaluating communication training and education in the field.
Patient‐specific risk factors of adverse drug events in adult inpatients – evidence detected using the Global Trigger Tool method
Authors: Härkänen Marja , Kervinen Marjo , Ahonen Jouni , Voutilainen Ari , Turunen Hannele , Vehviläinen‐Julkunen Katri
Published: November 2014

Aims and objectives

To identify the prevalence, preventability, and severity of adverse drug events in randomly selected adult hospital inpatients, and to study the association between adverse drug events and patient‐specific factors.

Background

Adverse drug events represent one of the major concerns in patient safety.

Design

A retrospective record review.

Methods

The study was conducted in an 800‐bed university hospital in Finland within a 12‐month period. Retrospective reviews of randomly selected discharged patients' (n = 463) records using the Global Trigger Tool method were undertaken. The prevalence, preventability, and severity of adverse drug events were studied, and the association between patient‐specific factors and adverse drug events were examined using a binary logistic regression model and Pearson's chi‐squared tests.

Results

A total of 180 adverse drug events were detected in 125 (27%) patients, of which 74 (41·1%) were preventable, and 94·4% caused temporary harm. An abnormal level of potassium in the blood was the most frequent adverse drug event (n = 37). The risk of adverse drug events increased with the length of hospital stay and the increased number of drugs patients used. The patients with coronary diseases (n = 130) had a 2·5 times higher risk of experiencing adverse drug events. In addition, the risk of adverse drug events during hospitalisation increased together with the co‐morbidity of patients.

Conclusions

Adverse drug events were experienced by a quarter of inpatients, while severe adverse drug events were rare. The risk of adverse drug events increased with patients' prolonged hospital stay, polypharmacy, and morbidity. In addition, information of the usefulness of the Global Trigger tool can be used for future development of the method.

Relevance to clinical practice

Patient‐specific risk factors were identified using the Global Trigger Tool method revealing that more efficient monitoring of inpatients with these risk factors may be profitable for decreasing adverse drug events.
A pioneer of Australian paediatrics: Dr Henry Edward Brown (1858–1931)
Authors: Isles Alan F , Roper Peter , Pearn John H
Published: November 2014

The emergence of paediatrics as a specialty in Australian medicine dates from the last two decades of the 19th century. Among the pioneers of pre‐Federation paediatrics, we include Dr Henry Edward Brown (1858–1931), an Irish‐born physician and surgeon who became the first paediatrician to practise in the northern half of the Australian continent. In 1885, he was appointed as the medical superintendent of the Rockhampton Children's Hospital, itself a pioneer institution in the care of sick and injured children. Dr H.E. Brown also served as medical officer of health concurrently in three Queensland shires. He was a leader in the literary and sporting life of the busy port town of Rockhampton and a scholar and significant philanthropist in the domain of French literature. His life was and remains an exemplar of a class of pre‐Federation paediatricians who established the ethos of clinical and societal service, which remains as a core feature of the speciality discipline of paediatrics in the 21st century.
Across the great divide: Proximate units at the lexical‐phonological interface
Authors: O'Séaghdha Padraig G.
Published: November 2014

Evidence that languages differ in the initial, proximate units of phonological encoding presents a challenge to current theories of language production. The proximate units principle is the idea that variation in the proximate, first selectable, phonological units during word form retrieval for speaking is key to understanding the implementation of phonological encoding in diverse languages. It proposes that rather than imposing a unilingual phonemic template across languages, the variety of proximate units should be incorporated in theories. From this perspective, cross‐linguistic differences in speech error patterns, in phonological preparation, in automatic activation, in multi‐word coordination, and in metalinguistic awareness are more clearly interpretable. The proximate units perspective aims to accelerate scientific progress by incorporating linguistic diversity at the lexical‐phonological interface into theories of word and sentence production.