Laterality and Flight: Concurrent Tests of Side-Bias and Optimality in Flying Tree Swallows

Behavioural side-bias occurs in many vertebrates, including birds as a result of hemispheric specialization and can be advantageous by improving response times to sudden stimuli and efficiency in multi-tasking. However, behavioural side-bias can lead to morphological asymmetries resulting in reduced performance for specific activities. For flying animals, wing asymmetry is particularly costly and it is unclear if behavioural side-biases will be expressed in flight; the benefits of quick response time afforded by side-biases must be balanced against the costs of less efficient flight due to the morphological asymmetry side-biases may incur. Thus, competing constraints could lead to context-dependent expression or suppression of side-bias in flight. In repeated flight trials through an outdoor tunnel with obstacles, tree swallows (Tachycineta bicolor) preferred larger openings, but we did not detect either individual or population-level side-biases. Thus, while observed behavioural side-biases during substrate-foraging and copulation are common in birds, we did not see such side-bias expressed in obstacle avoidance behaviour in flight. This finding highlights the importance of behavioural context for investigations of side-bias and hemispheric laterality and suggests both proximate and ultimate trade-offs between species-specific cognitive ecology and flight biomechanics

New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome.

The human protein kinome comprises 535 proteins that, with the exception of approximately 50 pseudokinases, control intracellular signaling networks by catalyzing the phosphorylation of multiple protein substrates. While a major research focus of the last 30 years has been cancer-associated Tyr and Ser/Thr kinases, over 85% of the kinome has been identified to be dysregulated in at least one disease or developmental disorder. Despite this remarkable statistic, for the majority of protein kinases and pseudokinases, there are currently no inhibitors progressing toward the clinic, and in most cases, details of their physiologic and pathologic mechanisms remain at least partially obscure. By curating and annotating data from the literature and major public databases of phosphorylation sites, kinases, and disease associations, we generate an unbiased resource that highlights areas of unmet need within the kinome. We discuss strategies and challenges associated with characterizing catalytic and noncatalytic outputs in cells, and describe successes and new frontiers that will support more comprehensive cancer-targeting and therapeutic evaluation in the future. Cancer Res; 78(1); 15-29. ©2017 AACR

Alteration of EGFR Spatiotemporal Dynamics Suppresses Signal Transduction

The epidermal growth factor receptor (EGFR), which regulates cell growth and survival, is integral to colon tumorigenesis. Lipid rafts play a role in regulating EGFR signaling, and docosahexaenoic acid (DHA) is known to perturb membrane domain organization through changes in lipid rafts. Therefore, we investigated the mechanistic link between EGFR function and DHA. Membrane incorporation of DHA into immortalized colonocytes altered the lateral organization of EGFR. DHA additionally increased EGFR phosphorylation but paradoxically suppressed downstream signaling. Assessment of the EGFR-Ras-ERK1/2 signaling cascade identified Ras GTP binding as the locus of the DHA-induced disruption of signal transduction. DHA also antagonized EGFR signaling capacity by increasing receptor internalization and degradation. DHA suppressed cell proliferation in an EGFR-dependent manner, but cell proliferation could be partially rescued by expression of constitutively active Ras. Feeding chronically-inflamed, carcinogen-injected C57BL/6 mice a fish oil containing diet enriched in DHA recapitulated the effects on the EGFR signaling axis observed in cell culture and additionally suppressed tumor formation. We conclude that DHA-induced alteration in both the lateral and subcellular localization of EGFR culminates in the suppression of EGFR downstream signal transduction, which has implications for the molecular basis of colon cancer prevention by DHA

Consistency and accuracy of diagnostic cancer codes generated by automated registration: comparison with manual registration

BACKGROUND: Automated procedures are increasingly used in cancer registration, and it is important that the data produced are systematically checked for consistency and accuracy. We evaluated an automated procedure for cancer registration adopted by the Lombardy Cancer Registry in 1997, comparing automatically-generated diagnostic codes with those produced manually over one year (1997). METHODS: The automatically generated cancer cases were produced by Open Registry algorithms. For manual registration, trained staff consulted clinical records, pathology reports and death certificates. The social security code, present and checked in both databases in all cases, was used to match the files in the automatic and manual databases. The cancer cases generated by the two methods were compared by manual revision. RESULTS: The automated procedure generated 5027 cases: 2959 (59%) were accepted automatically and 2068 (41%) were flagged for manual checking. Among the cases accepted automatically, discrepancies in data items (surname, first name, sex and date of birth) constituted 8.5% of cases, and discrepancies in the first three digits of the ICD-9 code constituted 1.6%. Among flagged cases, cancers of female genital tract, hematopoietic system, metastatic and ill-defined sites, and oropharynx predominated. The usual reasons were use of specific vs. generic codes, presence of multiple primaries, and use of extranodal vs. nodal codes for lymphomas. The percentage of automatically accepted cases ranged from 83% for breast and thyroid cancers to 13% for metastatic and ill-defined cancer sites. CONCLUSION: Since 59% of cases were accepted automatically and contained relatively few, mostly trivial discrepancies, the automatic procedure is efficient for routine case generation effectively cutting the workload required for routine case checking by this amount. Among cases not accepted automatically, discrepancies were mainly due to variations in coding practice

Does routine child health surveillance contribute to the early detection of children with pervasive developmental disorders? – An epidemiological study in Kent, U.K.

BACKGROUND: Recently changed guidelines for child health surveillance in the United Kingdom (U.K.) suggest targeted checks only, instead of the previously conducted routine or universal screening at 2 years and 3.5 years. There are concerns that these changes could lead to a delay in the detection of children with autism and other pervasive developmental disorders (PDD). Recent U.K. studies have suggested that the prevalence of PDD is much higher than previously estimated. This study establishes to which extent the routine checks contributed to the early detection and assessment of cases of PDD. Simultaneously we have evaluated the process involved and estimate the prevalence of PDD in our district. METHODS: Retrospective study design utilising community medical files. Headteachers of schools (n = 75) within Maidstone district (Kent) were asked to report all children with an established diagnosis of autism or PDD attending year 4 (born '91 and '92 / n = 2536) in October 2000 based on educational records. RESULTS: 59 schools (78.7%) took part in the study. A total of 33 children were reported. 21 fulfilled the inclusion criteria (12 falsely reported). The prevalences were (per 10,000): PDD 82.8 (male to female ratio 6:1), childhood autism 23.7, Asperger's syndrome 11.8 and autistic spectrum disorder 47.3. Co-existing medical conditions were noted in 14.3%; 52.4% were attending mainstream schools. In 63.2% of cases concerns – mainly in the area of speech and language development (SLD) – had been documented at the 2 year check. At the 3.5 year check concerns were noted in 94.1% – the main area was again SLD (76.5%), although behavioural abnormalities were becoming more frequent (47.1%). A total of 13 children (68.4%) were referred for further assessment as a direct result of the checks. CONCLUSIONS: The prevalences for different types of PDD were similar to figures published recently, but much higher than reported a few years ago. Analysis of our data suggests that routine surveillance is a valuable contributing factor for the early detection of PDD and thereby facilitates early intervention. Thus, if routine surveillance ceases, then an alternative method of early detection should be put in place

An audit and feedback intervention for reducing antibiotic prescribing in general dental practice:the RAPiD Cluster Randomised Controlled Trial

Acknowledgments: We thank the TRiaDS Research Methodology Group, including Irene Black, Debbie Bonetti, Heather Cassie, Martin Eccles, Sandra Eldridge, Jill J. Francis, Jeremy M. Grimshaw, Lorna Macpherson, Lorna McKee, Susan Michie, Nigel Pitts, Derek Richards, Douglas Stirling, Colin Tilley, Carole Torgerson, Shaun Treweek, Luke Vale, and Alan Walker for their guidance and contribution to the design and development of the study. We also thank Maria Prior for overseeing the running of the study, drafting of the published protocol, and her contribution to the design and analysis of the process evaluation. Thanks are also extended to Jill Farnham, Jenny Eades, Sarah Blackburn, and Lorna Barnsley for providing invaluable administrative support for this study. The views expressed in this article are those of the authors and may not reflect those of the funder. Funding: This study was conducted as part of the TRiaDS programme of implementation research which is funded by NHS Education for Scotland (NES). The Health Services Research Unit which is funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates supported the study. The funder had no influence over the design, conduct, analysis and write up of the study. Data Availability: Researchers can request to access the data from the Information Services Division of NHS National Services Scotland http://www.isdscotland.org/. Some restrictions may apply for the protection of privacy and appropriate usage of the data.Peer reviewedPublisher PD

Application of theory to enhance audit and feedback interventions to increase the uptake of evidence-based transfusion practice: an intervention development protocol

Background: Audits of blood transfusion demonstrate around 20% transfusions are outside national recommendations and guidelines. Audit and feedback is a widely used quality improvement intervention but effects on clinical practice are variable, suggesting potential for enhancement. Behavioural theory, theoretical frameworks of behaviour change and behaviour change techniques provide systematic processes to enhance intervention. This study is part of a larger programme of work to promote the uptake of evidence-based transfusion practice. Objectives: The objectives of this study are to design two theoretically enhanced audit and feedback interventions; one focused on content and one on delivery, and investigate the feasibility and acceptability. Methods: Study A (Content): A coding framework based on current evidence regarding audit and feedback, and behaviour change theory and frameworks will be developed and applied as part of a structured content analysis to specify the key components of existing feedback documents. Prototype feedback documents with enhanced content and also a protocol, describing principles for enhancing feedback content, will be developed. Study B (Delivery): Individual semi-structured interviews with healthcare professionals and observations of team meetings in four hospitals will be used to specify, and identify views about, current audit and feedback practice. Interviews will be based on a topic guide developed using the Theoretical Domains Framework and the Consolidated Framework for Implementation Research. Analysis of transcripts based on these frameworks will form the evidence base for developing a protocol describing an enhanced intervention that focuses on feedback delivery. Study C (Feasibility and Acceptability): Enhanced interventions will be piloted in four hospitals. Semi-structured interviews, questionnaires and observations will be used to assess feasibility and acceptability. Discussion: This intervention development work reflects the UK Medical Research Council’s guidance on development of complex interventions, which emphasises the importance of a robust theoretical basis for intervention design and recommends systematic assessment of feasibility and acceptability prior to taking interventions to evaluation in a full-scale randomised study. The work-up includes specification of current practice so that, in the trials to be conducted later in this programme, there will be a clear distinction between the control (usual practice) conditions and the interventions to be evaluated

Predictive value of PET response combined with baseline metabolic tumor volume in peripheral T-cell lymphoma patients

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive non-Hodgkin lymphomas with poor outcomes on current therapy. We investigated whether response assessed with PET/CT combined with baseline total metabolic tumor volume (TMTV) could detect early relapse or refractory disease. Methods: From 7 European centers, 140 patients with nodal PTCL who underwent baseline PET/CT were selected. Forty-three had interim PET (iPET) performed after 2 cycles (iPET2), 95 had iPET performed after 3 or 4 cycles (iPET3/4), and 96 had end-of-treatment PET (eotPET). Baseline TMTV was computed with a 41% SUVmax threshold, and PET response was reported using the Deauville 5-point scale. Results: With a median of 43 mo of follow-up, the 2-y progression-free survival (PFS) and overall survival (OS) were 51% and 67%, respectively. iPET2-positive patients (Deauville score ≥ 4) had a significantly worse outcome than iPET2-negative patients (P 230 cm3 and iPET3/4-negative [59%/84%]; TMTV ≤ 230 cm3 and iPET3/4-positive [42%/50%]; TMTV > 230 cm3 and iPET3/4-positive [0%/18%]). Conclusion: iPET response is predictive of outcome and allows early detection of high-risk PTCL patients. Combining iPET with TMTV improves risk stratification in individual patients

Impaired Resting-State Functional Integrations within Default Mode Network of Generalized Tonic-Clonic Seizures Epilepsy

Generalized tonic-clonic seizures (GTCS) are characterized by unresponsiveness and convulsions, which cause complete loss of consciousness. Many recent studies have found that the ictal alterations in brain activity of the GTCS epilepsy patients are focally involved in some brain regions, including thalamus, upper brainstem, medial prefrontal cortex, posterior midbrain regions, and lateral parietal cortex. Notably, many of these affected brain regions are the same and overlap considerably with the components of the so-called default mode network (DMN). Here, we hypothesize that the brain activity of the DMN of the GTCS epilepsy patients are different from normal controls, even in the resting state. To test this hypothesis, we compared the DMN of the GTCS epilepsy patients and the controls using the resting state functional magnetic resonance imaging. Thirteen brain areas in the DMN were extracted, and a complete undirected weighted graph was used to model the DMN for each participant. When directly comparing the edges of the graph, we found significant decreased functional connectivities within the DMN of the GTCS epilepsy patients comparing to the controls. As for the nodes of the graph, we found that the degree of some brain areas within the DMN was significantly reduced in the GTCS epilepsy patients, including the anterior medial prefrontal cortex, the bilateral superior frontal cortex, and the posterior cingulate cortex. Then we investigated into possible mechanisms of how GTCS epilepsy could cause the reduction of the functional integrations of DMN. We suggested the damaged functional integrations of the DMN in the GTCS epilepsy patients even during the resting state, which could help to understand the neural correlations of the impaired consciousness of GTCS epilepsy patients

Combined use of the Consolidated Framework for Implementation Research (CFIR) and the Theoretical Domains Framework (TDF): A systematic review

Background: Over 60 implementation frameworks exist. Using multiple frameworks may help researchers to address multiple study purposes, levels, and degrees of theoretical heritage and operationalizability; however, using multiple frameworks may result in unnecessary complexity and redundancy if doing so does not address study needs. The Consolidated Framework for Implementation Research (CFIR) and the Theoretical Domains Framework (TDF) are both well-operationalized, multi-level implementation determinant frameworks derived from theory. As such, the rationale for using the frameworks in combination (i.e., CFIR + TDF) is unclear. The objective of this systematic review was to elucidate the rationale for using CFIR + TDF by (1) describing studies that have used CFIR + TDF, (2) how they used CFIR + TDF, and (2) their stated rationale for using CFIR + TDF. Methods: We undertook a systematic review to identify studies that mentioned both the CFIR and the TDF, were written in English, were peer-reviewed, and reported either a protocol or results of an empirical study in MEDLINE/PubMed, PsycInfo, Web of Science, or Google Scholar. We then abstracted data into a matrix and analyzed it qualitatively, identifying salient themes. Findings: We identified five protocols and seven completed studies that used CFIR + TDF. CFIR + TDF was applied to studies in several countries, to a range of healthcare interventions, and at multiple intervention phases; used many designs, methods, and units of analysis; and assessed a variety of outcomes. Three studies indicated that using CFIR + TDF addressed multiple study purposes. Six studies indicated that using CFIR + TDF addressed multiple conceptual levels. Four studies did not explicitly state their rationale for using CFIR + TDF. Conclusions: Differences in the purposes that authors of the CFIR (e.g., comprehensive set of implementation determinants) and the TDF (e.g., intervention development) propose help to justify the use of CFIR + TDF. Given that the CFIR and the TDF are both multi-level frameworks, the rationale that using CFIR + TDF is needed to address multiple conceptual levels may reflect potentially misleading conventional wisdom. On the other hand, using CFIR + TDF may more fully define the multi-level nature of implementation. To avoid concerns about unnecessary complexity and redundancy, scholars who use CFIR + TDF and combinations of other frameworks should specify how the frameworks contribute to their study. Trial registration: PROSPERO CRD4201502761