The effect of volumetric breast density on the risk of screen-detected and interval breast cancers: a cohort study.

BACKGROUND: In the light of the breast density legislation in the USA, it is important to know a woman's breast cancer risk, but particularly her risk of a tumor that is not detected through mammographic screening (interval cancer). Therefore, we examined the associations of automatically measured volumetric breast density with screen-detected and interval cancer risk, separately. METHODS: Volumetric breast measures were assessed automatically using Volpara version 1.5.0 (Matakina, New Zealand) for the first available digital mammography (DM) examination of 52,814 women (age 50 - 75 years) participating in the Dutch biennial breast cancer screening program between 2003 and 2011. Breast cancer information was obtained from the screening registration system and through linkage with the Netherlands Cancer Registry. We excluded all screen-detected breast cancers diagnosed as a result of the first digital screening examination. During a median follow-up period of 4.2 (IQR 2.0-6.2) years, 523 women were diagnosed with breast cancer of which 299 were screen-detected and 224 were interval breast cancers. The associations between volumetric breast measures and breast cancer risk were determined using Cox proportional hazards analyses. RESULTS: Percentage dense volume was found to be positively associated with both interval and screen-detected breast cancers (hazard ratio (HR) 8.37 (95% CI 4.34-16.17) and HR 1.39 (95% CI 0.82-2.36), respectively, for Volpara density grade category (VDG) 4 compared to VDG1 (p for heterogeneity < 0.001)). Dense volume (DV) was also found to be positively associated with both interval and screen-detected breast cancers (HR 4.92 (95% CI 2.98-8.12) and HR 2.30 (95% CI 1.39-3.80), respectively, for VDG-like category (C)4 compared to C1 (p for heterogeneity = 0.041)). The association between percentage dense volume categories and interval breast cancer risk (HR 8.37) was not significantly stronger than the association between absolute dense volume categories and interval breast cancer risk (HR 4.92). CONCLUSIONS: Our results suggest that both absolute dense volume and percentage dense volume are strong markers of breast cancer risk, but that they are even stronger markers for predicting the occurrence of tumors that are not detected during mammography breast cancer screening

The challenges faced in the design, conduct and analysis of surgical randomised controlled trials

Randomised evaluations of surgical interventions are rare; some interventions have been widely adopted without rigorous evaluation. Unlike other medical areas, the randomised controlled trial (RCT) design has not become the default study design for the evaluation of surgical interventions. Surgical trials are difficult to successfully undertake and pose particular practical and methodological challenges. However, RCTs have played a role in the assessment of surgical innovations and there is scope and need for greater use. This article will consider the design, conduct and analysis of an RCT of a surgical intervention. The issues will be reviewed under three headings: the timing of the evaluation, defining the research question and trial design issues. Recommendations on the conduct of future surgical RCTs are made. Collaboration between research and surgical communities is needed to address the distinct issues raised by the assessmentof surgical interventions and enable the conduct of appropriate and well-designed trials.The Health Services Research Unit is funded by the Scottish Government Health DirectoratesPeer reviewedPublisher PD

Defining the phenotypical spectrum associated with variants in TUBB2A

Background Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis. Methods In order to further refine the phenotypical spectrum associated with TUBB2A, clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed. Results We report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy. Conclusion The imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype-phenotype correlations could be established, suggesting the role of additional modifiers.</p

A study to explore if dentists’ anxiety affects their clinical decision-making

Aims To develop a measure of dentists’ anxiety in clinical situations; to establish if dentists’ anxiety in clinical situations affected their self-reported clinical decision-making; to establish if occupational stress, as demonstrated by burnout, is associated with anxiety in clinical situations and clinical decision-making; and to explore the relationship between decision-making style and the clinical decisions which are influenced by anxiety. Design Cross-sectional study. Setting Primary Dental Care. Subjects and methods A questionnaire battery [Maslach Burnout Inventory, measuring burnout; Melbourne Decision Making Questionnaire, measuring decision-making style; Dealing with Uncertainty Questionnaire (DUQ), measuring coping with diagnostic uncertainty; and a newly designed Dentists’ Anxieties in Clinical Situations Scale, measuring dentists’ anxiety (DACSS-R) and change of treatment (DACSS-C)] was distributed to dentists practicing in Nottinghamshire and Lincolnshire. Demographic data were collected and dentists gave examples of anxiety-provoking situations and their responses to them. Main outcome measure Respondents’ self-reported anxiety in various clinical situations on a 11-point Likert Scale (DACSS-R) and self-reported changes in clinical procedures (Yes/No; DACSS-C). The DACSS was validated using multiple t-tests and a principal component analysis. Differences in DACSS-R ratings and burnout, decision-making and dealing with uncertainty were explored using Pearson correlations and multiple regression analysis. Qualitative data was subject to a thematic analysis. Results The DACSS-R revealed a four-factor structure and had high internal reliability (Cronbach’s α = 0.94). Those with higher DACSS-R scores of anxiety were more likely to report changes in clinical procedures (DACSS-C scores). DACSS-R scores were associated with decision-making self-esteem and style as measured by the MDMQ and all burnout subscales, though not with scores on the DUQ scale. Conclusion Dentists’ anxiety in clinical situations does affect the way that dentists work clinically, as assessed using the newly designed and validated DACSS. This anxiety is associated with measures of burnout and decision-making style with implications for training packages for dentists

Assistive technology assessment and planning for children with multiple disabilities in educational settings

A number of critical elements have been identified in assistive technology assessment and planning to optimise its integration into the educational environments of children and hence address their functional goals. These elements are as follows: adopting a collaborative think-tank team approach to which all educational team members contribute equally and where technology experts are consulted once the need for specific technical support or training is identified; involving the family by establishing mutual expectations and using effective communication strategies; and conducting in-depth assessment that identifies clear goals, includes task analysis within daily environments, examines the child-device interaction closely and investigates the resources available to implement assistive technology use. With this backdrop, this paper reviews existing assessments and proposes that the Lifespace Access Profile (LAP) (Williams et al 1993) and Lifespace Access Profile (Upper Extension) (LAPUE) (Williams et al 1994) satisfy many of the criteria for effective assessment and planning advocated in the literature

Defining the phenotypical spectrum associated with variants in TUBB2A

Background Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis. Methods In order to further refine the phenotypical spectrum associated with TUBB2A, clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed. Results We report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy. Conclusion The imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype-phenotype correlations could be established, suggesting the role of additional modifiers.</p

Species-specific behavioral patterns correlate with differences in synaptic connections between homologous mechanosensory neurons

We characterized the behavioral responses of two leech species, Hirudo verbana and Erpobdella obscura, to mechanical skin stimulation and examined the interactions between the pressure mechanosensory neurons (P cells) that innervate the skin. To quantify behavioral responses, we stimulated both intact leeches and isolated body wall preparations from the two species. In response to mechanical stimulation, Hirudo showed local bending behavior, in which the body wall shortened only on the side of the stimulation. Erpobdella, in contrast, contracted both sides of the body in response to touch. To investigate the neuronal basis for this behavioral difference, we studied the interactions between P cells. Each midbody ganglion has four P cells; each cell innervates a different quadrant of the body wall. Consistent with local bending, activating any one P cell in Hirudo elicited polysynaptic inhibitory potentials in the other P cells. In contrast, the P cells in Erpobdella had excitatory polysynaptic connections, consistent with the segment-wide contraction observed in this species. In addition, activating individual P cells caused asymmetrical body wall contractions in Hirudo and symmetrical body wall contractions in Erpobdella. These results suggest that the different behavioral responses in Erpobdella and Hirudo are partly mediated by interactions among mechanosensory cells

Foreign policy and globalization theory: The case of Israel

Since the early 1990s, international relations has witnessed a stimulating debate on globalization. This debate laid the foundations for globalization theory (GT), providing the tools for an empirical examination of the globalization of multiple activities: from politics and organized violence, to finance, trade and production, through culture and environmental degradation. However, examination of what appear to be the best-known works on globalization reveals that foreign policy has been virtually excluded from GT. In this context, based on what is described here as a synergistic transformationalist approach (STA) to globalization, I provide a critique of GT. The critique is geared towards examining why foreign policy hitherto has been overlooked by contemporary GT. I expose the problems this generates and address them by exploring how STA enables GT to incorporate foreign policy. I use the case of Israel heuristically to elicit how incorporating foreign policy into GT may provide a better understanding of the relationship between foreign policy and globalization. Three themes are highlighted: the role of foreign policy in inducing and reproducing globalization; determining the mutually constitutive relationship between globalization and the state; and shaping the interfacing between international politics and globalization

How I report breast magnetic resonance imaging studies for breast cancer staging and screening

Magnetic resonance imaging (MRI) of the breast is the most sensitive imaging technique for the diagnosis and local staging of primary breast cancer and yet, despite the fact that it has been in use for 20 years, there is little evidence that its widespread uncritical adoption has had a positive impact on patient-related outcomes. This has been attributed previously to the low specificity that might be expected with such a sensitive modality, but with modern techniques and protocols, the specificity and positive predictive value for malignancy can exceed that of breast ultrasound and mammography. A more likely explanation is that historically, clinicians have acted on MRI findings and altered surgical plans without prior histological confirmation. Furthermore, modern adjuvant therapy for breast cancer has improved so much that it has become a very tall order to show a an improvement in outcomes such as local recurrence rates. In order to obtain clinically useful information, it is necessary to understand the strengths and weaknesses of the technique and the physiological processes reflected in breast MRI. An appropriate indication for the scan, proper patient preparation and good scan technique, with rigorous quality assurance, are all essential prerequisites for a diagnostically relevant study. The use of recognised descriptors from a standardised lexicon is helpful, since assessment can then dictate subsequent recommendations for management, as in the American College of Radiology BI-RADS (Breast Imaging Reporting and Data System) lexicon (Morris et al., ACR BI-RADS® Atlas, Breast Imaging Reporting and Data System, 2013). It also enables audit of the service. However, perhaps the most critical factor in the generation of a meaningful report is for the reporting radiologist to have a thorough understanding of the clinical question and of the findings that will influence management. This has never been more important than at present, when we are in the throes of a remarkable paradigm shift in the treatment of both early stage and locally advanced breast cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40644-016-0078-0) contains supplementary material, which is available to authorized users