ALK translocation is associated with ALK immunoreactivity and extensive signet-ring morphology in primary lung adenocarcinoma.

BACKGROUND: ALK rearrangement is particularly observed in signet-ring sub-type adenocarcinoma. Since fluorescence in situ hybridization (FISH) is not suitable for mass screening, we aimed to characterize the predictive utility of tumour morphology and ALK immunoreactivity to identify ALK rearrangement, in a primary lung adenocarcinoma dataset enriched for signet-ring morphology, compared with that of other morphology. METHODS: 7 adenocarcinomas from diagnostic archives reported with signet-ring morphology were assessed and compared with 11 adenocarcinomas without signet-ring features over the same time period. Growth patterns were reviewed, ALK expression was assessed by standard immunohistochemistry using ALK1 clone and Envision detection (Dako), and ALK rearrangement was assessed by FISH (Abbott Molecular). Associations between groups and predictive utility of tumour morphology and ALK expression using FISH as gold standard were calculated. RESULTS: 2 excision lung biopsy cases with pure (100%) signet-ring morphology and solid patterns demonstrated diffuse moderate cytoplasmic ALK immunoreactivity (2+) and harboured ALK rearrangements (p=0.007), unlike 5 mixed-signet-ring and 11 non-signet-ring adenocarcinomas, which showed negative or 1+ immunoreactivity; and did not harbour ALK rearrangements (p>0.1). ALK expression was not associated with ALK copy number. 6 of 7 cases with signet ring morphology stained for TTF-1. Pure signet-ring morphology and moderate ALK expression were both associated with ALK rearranged tumours. CONCLUSION: ALK rearrangement is strongly associated with ALK immunoreactivity, and was seen only in tumours with pure signet-ring morphology and solid growth pattern. Tumour morphology, growth pattern and ALK immunoreactivity appear to be good indicators of ALK rearrangement, with TTF-1 positivity aiding in proving primary pulmonary origin.

PIPc study: development of indicators of potentially inappropriate prescribing in children (PIPc) in primary care using a modified Delphi technique

Objective There is limited evidence regarding the quality of prescribing for children in primary care. Several prescribing criteria (indicators) have been developed to assess the appropriateness of prescribing in older and middle-aged adults but few are relevant to children. The objective of this study was to develop a set of prescribing indicators that can be applied to prescribing or dispensing data sets to determine the prevalence of potentially inappropriate prescribing in children (PIPc) in primary care settings.


Design Two-round modified Delphi consensus method.


Setting Irish and UK general practice.


Participants A project steering group consisting of academic and clinical general practitioners (GPs) and pharmacists was formed to develop a list of indicators from literature review and clinical expertise. 15 experts consisting of GPs, pharmacists and paediatricians from the Republic of Ireland and the UK formed the Delphi panel.


Results 47 indicators were reviewed by the project steering group and 16 were presented to the Delphi panel. In the first round of this exercise, consensus was achieved on nine of these indicators. Of the remaining seven indicators, two were removed following review of expert panel comments and discussion of the project steering group. The second round of the Delphi process focused on the remaining five indicators, which were amended based on first round feedback. Three indicators were accepted following the second round of the Delphi process and the remaining two indicators were removed. The final list consisted of 12 indicators categorised by respiratory system (n=6), gastrointestinal system (n=2), neurological system (n=2) and dermatological system (n=2).


Conclusions The PIPc indicators are a set of prescribing criteria developed for use in children in primary care in the absence of clinical information. The utility of these criteria will be tested in further studies using prescribing databases.

Exploring the impact of depressive symptoms and medication beliefs on medication adherence in hypertension-A primary care study

Objective: This Study aimed to assess the levels of adherence in a sample of hypertensive patients being cared for in primary care in Northern Ireland and to explore the impact of depressive symptoms and medication beliefs on medication adherence.

Children’s perceptions of primary science assessment in England and Wales

This study builds on and contributes to work on assessment of children in primary school, particularly in science. Previous research has examined primary science assessment from different standpoints, but no studies have speci?cally addressed children’s perspectives. This article provides additional insight into issues surrounding children’s assessment in primary school and how the assessment of science might develop in England after the science SATs (Standard Assessment Tests) were abolished in 2009. Some research suggests that primary science assessment via SATs is a major reason for the observed decline in children’s engagement with science in upper primary and lower secondary school. The analytic focus on engaging children as coresearchers to assist in the process of gathering informed views and interpreting ?ndings from a large sample of children’s views enables another contribution. The study, based on a survey of 1000 children in primary and secondary schools in England and Wales, reveals that despite being assessed under two different regimes (high-stakes national tests in England and moderated teacher assessment in Wales), children’s views of science assessment are remarkably consistent. Most appreciate the usefulness of science assessment and value frequent, non-SATs testing for monitoring/improving science progress. There was a largely negative impact, however, of science
assessment on children’s well-being, particularly due to stress. The paper demonstrates that children provide an important perspective on assessment and that including their views can improve policy-making in relation to primary science assessment.

Heat shock protein 90 inhibition is cytotoxic to primary AML cells expressing mutant FLT3 and results in altered downstream signalling

Activating mutations of the FMS-like tyrosine kinase 3 gene (FLT3) occur in approximately one-third of patients with acute myeloid leukaemia (AML) and predict for a poor outcome. Heat shock protein 90 (Hsp90) is a molecular chaperone that is frequently used by cancer cells to stabilise mutant oncoproteins. Mutant FLT3 is chaperoned by Hsp90 in primary AML blasts whereas unmutated FLT3 is not, making Hsp90 inhibitors potentially useful therapeutically. The present study showed that inhibition of Hsp90 by 17-allylamino-17-demethoxygeldanamycin (17-AAG) was cytotoxic to primary AML cells expressing mutant FLT3. Inhibition of Hsp90 results in altered downstream signalling effects in primary AML cells with disruption of Janus kinase-signal transducer and activator of transcription (JAK-STAT), mitogen-activated protein kinase and phosphatidylinositol 3/AKT signalling pathways. Co-treatment of blasts with 17-AAG and cytarabine resulted in a synergistic or additive effect in approximately 50% of AML cases tested. Our results confirm that Hsp90 is a valid molecular target in the therapy of AML. Inhibition of Hsp90 in parallel with conventional AML therapies may have particular benefit in those patients with the poor prognostic FLT3 mutant disease.

Organizational culture predicts job satisfaction and perceived clinical effectiveness in pediatric primary care practices

Background: In recent years, there has been a growing understanding that organizational culture is related to an organization's performance. However, fewstudies have examined organizational culture in medical group practices. Objectives: The purpose of this study was to examine the relationship of organizational culture on provider job satisfaction and perceived clinical effectiveness in primary care pediatric practices. Research Design: This cross-sectional study included 36 primary care pediatric practices located in Connecticut. Participants: There were 374 participants in this study, which included 127 clinicians and 247 nonclinicians. Measures: Office managers completed a questionnaire that recorded staff and practice characteristics; all participants completed the Organizational Culture Scale, a questionnaire that assessed the practice on four cultural domains (i.e., group, developmental, rational, and hierarchical), and the Primary Care Organizational Questionnaire that evaluated perceived effectiveness and job satisfaction. Results: Hierarchical linear models using a restricted maximum likelihood estimation method were used to evaluate whether the practice culture types predicted job satisfaction and perceived effectiveness. Group culture was positively associated with both satisfaction and perceived effectiveness. In contrast, hierarchical and rational culture were negatively associated with both job satisfaction and perceived effectiveness. These relationships were true for clinicians, nonclinicians, and the practice as a whole. Conclusions: Our study demonstrates that practice culture is associated with job satisfaction and perceived clinical effectiveness and that a group culture was associated with high job satisfaction and perceived effectiveness. Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Cooperative Learning in Science: Follow-up from primary to high school

This paper reports a two-year longitudinal study of the effects of cooperative learning on science attainment, attitudes towards science, and social connectedness during transition from primary to high school. A previous project on cooperative learning in primary schools observed gains in science understanding and in social aspects of school life. This project followed 204 children involved in the previous project and 440 comparison children who were not as they undertook transition from 24 primary schools to 16 high schools. Cognitive, affective, and social gains observed in the original project survived transition. The implications improving the effectiveness of school transition by using cooperative learning initiatives are explored. Possibilities for future research and the implications for practice and policy are discussed.

Outcomes and process in reading tutoring

Background: Large-scale randomised controlled trials are relatively rare in education. The present study approximates to, but is not exactly, a randomised controlled trial. It was an attempt to scale up previous small peer tutoring projects, while investing only modestly in continuing professional development for teachers.Purpose: A two-year study of peer tutoring in reading was undertaken in one local education authority in Scotland. The relative effectiveness of cross-age versus same-age tutoring, light versus intensive intervention, and reading versus reading and mathematics tutoring were investigated.Programme description (if relevant): The intervention was Paired Reading, a freely available cross-ability tutoring method applied to books of the pupils' choice but above the tutee's independent readability level. It involves Reading Together and Reading Alone, and switching from one to the other according to need.Sample: Eighty-seven primary schools of overall average socio-economic status, ability and gender in one council in Scotland. There were few ethnic minority students. Proportions of students with special needs were low. Children were eight and 10 years old as the intervention started. Macro-evaluation n = 3520. Micro-evaluation Year 1 15 schools n = 592, Year 2 a different 15 schools n = 591, compared with a comparison group of five schools n = 240.Design and methods: Almost all the primary schools in the local authority participated and were randomly allocated to condition. A macro-evaluation tested and retested over a two-year period using Performance Indicators in Primary Schools. A micro-evaluation tested and retested within each year using norm-referenced tests of reading comprehension. Macro-evaluation was with multi-level modelling, micro-evaluation with descriptive statistics and effect sizes, analysis of variance (ANOVA) and multivariate analysis of variance (MANOVA).Results: Macro-evaluation yielded significant pre-post gains in reading attainment for cross-age tutoring over both years. No other differences were significant. Micro-evaluation yielded pre-post changes in Year 1 (selected) and Year 2 (random) greater than controls, with no difference between same-age and cross-age tutoring. Light and intensive tutoring were equally effective. Tutoring reading and mathematics together was more effective than only tutoring reading. Lower socio-economic and lower reading ability students did better. Girls did better than boys. Regarding observed implementation quality, some factors were high and others low. Few implementation variables correlated with attainment gain.Conclusions: Paired Reading tutoring does lead to better reading attainment compared with students not participating. This is true in the long term (macro-evaluation) for cross-age tutoring, and in the short term (micro-evaluation) for both cross-age and same-age tutoring. Tutors and tutees benefited. Intensity had no effect but dual tutoring did have an effect. Low-socio-economic status, low-ability and female students did better. The results of the different forms of evaluation were indeed different. There are implications for practice and for future research. © 2012 Copyright Taylor and Francis Group, LLC.

SMAD inhibition attenuates epithelial to mesenchymal transition by primary keratinocytes in vitro

Epithelial to mesenchymal transition (EMT) is a process whereby epithelial cells undergo transition to a mesenchymal phenotype and contribute directly to fibrotic disease. Recent studies support a role for EMT in cutaneous fibrotic diseases including scleroderma and hypertrophic scarring, though there is limited data on the cytokines and signalling mechanisms regulating cutaneous EMT. We investigated the ability of TGF-β and TNF-α, both over-expressed in cutaneous scleroderma and central mediators of EMT in other epithelial cell types, to induce EMT in primary keratinocytes and studied the signalling mechanisms regulating this process. TGF-β induced EMT in normal human epidermal keratinocytes (NHEK cells) and this process was enhanced by TNF-α. EMT was characterised by changes in morphology, proteome (down-regulation of E-cadherin and Zo-1, and up-regulation of vimentin and fibronectin), MMP secretion and COL1α1 mRNA expression. TGF-β and TNF-α in combination activated SMAD and p38 signalling in NHEK cells. P38 inhibition with SB203580 partially attenuated EMT, whereas SMAD inhibition using SB431542 significantly inhibited EMT and also reversed established EMT. These data highlight the retained plasticity of adult keratinocytes and support further studies of EMT in clinically relevant in vivo models of cutaneous fibrosis, and investigation of SMAD inhibition as a potential therapeutic intervention. This article is protected by copyright. All rights reserved.

Perceptions of collaboration between general practitioners and community pharmacists: Findings from a qualitative study based in Spain

According to the theory of reasoned action (TRA), collaboration is only possible when it is perceived as useful by the participants involved. This paper describes a qualitative study using semi-structured interviews to explore the preceived usefulness of general practitioner (GPs)-community pharmacists (CPs)' collaboration from these professionals' perspectives based in two Spanish regions. Thirty-seven interviews were conducted with GPs and CPs with and without previous experience of collaborating with the other groups of professionals. Analysis of the data indicated that the GPs and CPs considered that collaboration between practitioners and pharmacists to have different forms of usefulness, ranging from positive to negative perceptions of usefulness. Negative and neutral opinions (collaboration generates conflict and/or is not benefitial) could prevent practitioners from initiating collaboration with the other group of professionals, which is explained by the TRA. These perceptions were only found among those participants without experience in collaboration. When collaboration was perceived as advantageous, it could be beneficial on three levels: health system (i.e. provision of integrated care, increased efficiency of the system), GPs and CPs (i.e. increased job satisfaction and patient loyalty) and patients (i.e. improved patient safety). Although GPs and CPs with experience identified benefits using a range of examples, GPs and CPs who had never collaborated also believed that if collaboration was undertaken there would be benefits for the health system, patients and health professionals. These results should be considered when developing strategies to encourage and improve the implementation of collaborative working relationships between GPs and pharmacists in primary care.

Characterisation of the frequent exacerbator phenotype in COPD patients in a large UK primary care population

BACKGROUND: The 'frequent exacerbator' is recognised as an important phenotype in COPD. Current understanding about this phenotype comes from prospective longitudinal clinical trials in secondary/tertiary care with little information reported in primary care populations.

AIMS: To characterize the frequent-exacerbator phenotype and identify associated risk factors in a large UK primary care COPD population.

METHODS: Using a large database of primary care patients from 80 UK general practices, patients were categorised using GOLD 2014 criteria into high and low risk groups based on exacerbation history. A multivariate logistic regression model was used to investigate covariates associated with the frequent-exacerbator phenotype and risk of experiencing a severe exacerbation (leading to hospitalisation).

RESULTS: Of the total study population (n = 9219), 2612 (28%) fulfilled the criteria for high risk frequent-exacerbators. Independent risk factors (adjusted odds ratio [95% CI]) for ≥2 exacerbations were: most severely impaired modified Medical Research Council (mMRC) dyspnoea score (mMRC grade 4: 4.37 [2.64-7.23]), lower FEV1 percent predicted (FEV1 <30%: 2.42 [1.61-3.65]), co-morbid cardiovascular disease (1.42 [1.19-1.68]), depression (1.56 [1.22-1.99]) or osteoporosis (1.54 [1.19-2.01]), and female gender (1.20 [1.01-1.43]). Older patients (≥75 years), those with most severe lung impairment (FEV1 <30%), those with highest mMRC score and those with co-morbid osteoporosis were identified as most at risk of experiencing exacerbations requiring hospitalisation.

CONCLUSIONS: Although COPD exacerbations occur across all grades of disease severity, female patients with high dyspnoea scores, more severely impaired lung function and co-morbidities are at greatest risk. Elderly patients, with severely impaired lung function, high mMRC scores and osteoporosis are associated with experience of severe exacerbations requiring hospitalisation.

Digital slide viewing for primary reporting in gastrointestinal pathology: a validation study

Despite the increasing availability of digital slide viewing, and numerous advantages associated with its application, a lack of quality validation studies is amongst the reasons for poor uptake in routine practice. This study evaluated primary digital pathology reporting in the setting of routine subspecialist gastrointestinal pathology, commonplace in most tissue pathology laboratories and representing one of the highest volume specialties in most laboratories. Individual digital and glass slide diagnoses were compared amongst three pathologists reporting in a gastrointestinal subspecialty team, in a prospective series of 100 consecutive diagnostic cases from routine practice in a large teaching hospital laboratory. The study included a washout period of at least 6 months. Discordant diagnoses were classified, and the study evaluated against recent College of American Pathologists (CAP) recommendations for evaluating digital pathology systems for diagnostic use. The study design met all 12 of the CAP recommendations. The 100 study cases generated 300 pairs of diagnoses, comprising 100 glass slide diagnoses and 100 digital diagnoses from each of the three study pathologists. 286 of 300 pairs of diagnoses were concordant, representing intraobserver concordance of 95.3 %, broadly comparable to rates previously published in this field. In ten of the 14 discordant pairs, the glass slide diagnosis was favoured; in four cases, the digital diagnosis was favoured, but importantly, the 14 discordant intraobserver diagnoses were considered to be of minor clinical significance. Interobserver, or viewing modality independent, concordance was found in 94 of the total of 100 study cases, providing a comparable baseline discordance rate expected in any second viewing of pathology material. These overall results support the safe use of digital pathology in primary diagnostic reporting in this setting

Corneal biomechanics, refractive error, and axial length in Chinese primary school children.

PURPOSE: Low corneal hysteresis is associated with longer axial length in Chinese secondary school children. The authors sought to explore this association in primary school children. METHODS: LogMAR presenting visual acuity, cycloplegic refractive error, ocular biometry, central corneal thickness (CCT), and corneal hysteresis (CH) was assessed for children in grades 1 to 3 at an academically competitive urban school in Shantou, China. RESULTS: Among 872 eligible children (mean age, 8.6 ± 2.1 years), 651 (74.7%) completed the examination. Among 1299 examined eyes, 111 (8.5%) had uncorrected vision ≤6/12. Mean spherical equivalent refractive error for all eyes was +0.26 ± 1.41 D, and axial length (AL) was 22.7 ± 0.90 mm. CH for the lowest (mean AL, 21.7 ± 0.39 mm), two middle (mean AL, 22.4 ± 0.15 and 22.9 ± 0.15 mm), and highest quartiles (mean AL, 23.7 ± 0.74 mm) of AL were 10.6 ± 2.1 mm Hg, 10.4 ± 2.1 mm Hg, 10.3 ± 2.3 mm Hg, and 10.2 ± 2.3 mm Hg respectively (age- and gender-adjusted Pearson's correlation coefficient r = -0.052; P = 0.001). In generalized estimating equation models adjusting for age, gender, and CCT, lower CH was significantly associated with longer AL (P < 0.001) and more myopic refractive error (P = 0.001). CONCLUSIONS: CH measurement is practical in young children because this is when myopia undergoes its most rapid progression. Prospective follow-up of this cohort at high risk for myopia is under way to determine whether low CH is predictive, or a consequence, of long AL.

Validating the accuracy of a model to predict the onset of myopia in children.

PURPOSE: To assess the sensitivity and specificity of models predicting myopia onset among ethnically Chinese children. METHODS: Visual acuity, height, weight, biometry (A-scan, keratometry), and refractive error were assessed at baseline and 3 years later using the same equipment and protocol in primary schools in Xiamen (China) and Singapore. A regression model predicting the onset of myopia < -0.75 diopters (D) after 3 years in either eye among Xiamen children was validated with Singapore data. RESULTS: Baseline data were collected from 236 Xiamen children (mean age, 7.82 ± 0.63 years) and from 1979 predominantly Chinese children in Singapore (7.83 ± 0.84 years). Singapore children were significantly taller and heavier, and had more myopia (31.4% vs. 6.36% < -0.75 D in either eye, P < 0.001) and longer mean axial length. Three-year follow-up was available for 80.0% of Xiamen children and 83.1% in Singapore. For Xiamen, the area under the receiver-operator curve (AUC) in a model including ocular biometry, height, weight, and presenting visual acuity was 0.974 (95% confidence interval [CI], 0.945-0.997). In Singapore, the same model achieved sensitivity, specificity, and positive predictive value of 0.844, 0.650, and 0.669, with an AUC of 0.815 (95% CI, 0.791-0.839). CONCLUSIONS: Accuracy in predicting myopia onset based on simple measurements may be sufficient to make targeted early intervention practical in settings such as Singapore with high myopia prevalence. Models based on cohorts with a greater prevalence of high myopia than that in Xiamen could be used to assess accuracy of models predicting more severe forms of myopia.