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A major challenge for coral reef conservation and management is understanding how a wide range of interacting human and natural drivers cumulatively impact and shape these ecosystems. Despite the importance of understanding these interactions, a methodological framework to synthesize spatially explicit data of such drivers is lacking. To fill this gap, we established a transferable data synthesis methodology to integrate spatial data on environmental and anthropogenic drivers of coral reefs, and applied this methodology to a case study location-the Main Hawaiian Islands (MHI). Environmental drivers were derived from time series (2002-2013) of climatological ranges and anomalies of remotely sensed sea surface temperature, chlorophyll-a, irradiance, and wave power. Anthropogenic drivers were characterized using empirically derived and modeled datasets of spatial fisheries catch, sedimentation, nutrient input, new development, habitat modification, and invasive species. Within our case study system, resulting driver maps showed high spatial heterogeneity across the MHI, with anthropogenic drivers generally greatest and most widespread on O'ahu, where 70% of the state's population resides, while sedimentation and nutrients were dominant in less populated islands. Together, the spatial integration of environmental and anthropogenic driver data described here provides a first-ever synthetic approach to visualize how the drivers of coral reef state vary in space and demonstrates a methodological framework for implementation of this approach in other regions of the world. By quantifying and synthesizing spatial drivers of change on coral reefs, we provide an avenue for further research to understand how drivers determine reef diversity and resilience, which can ultimately inform policies to protect coral reefs.

Purpose: Patients must be able to feel as much trust for caregivers and the healthcare system at the healthcare centre as at the emergency department. The aim of this study is to explain and understand the phenomenon of trust in the early chain of healthcare, when a patient has called an ambulance for a non-urgent condition and been referred to the healthcare centre., Method: A lifeworld hermeneutic approach from the perspective of caring science was used. Ten patients participated: seven female and three male. The setting is the early chain of healthcare in south-western Sweden., Results: The findings show that the phenomenon of trust does not automatically involve medical care. However, attention to the patient's lifeworld in a professional caring relationship enables the patient to trust the caregiver and the healthcare environment. It is clear that the "voice of the lifeworld" enables the patient to feel trust., Conclusion: Trust in the early chain of healthcare entails caregivers' ability to pay attention to both medical and existential issues in compliance with the patient's information and questions. Thus, the patient must be invited to participate in assessments and decisions concerning his or her own healthcare, in a credible manner and using everyday language.

Despite early reports and the contemporary consensus on microsaccades as purely binocular phenomena, recent work has proposed not only the existence of monocular microsaccades, but also that they serve functional purposes. We take a critical look at the detection of monocular microsaccades from a signal perspective, using raw data and a state-of-the-art, video-based eye tracker. In agreement with previous work, monocular detections were present in all participants using a standard microsaccade detection algorithm. However, a closer look at the raw data invalidates the vast majority of monocular detections. These results again raise the question of the existence of monocular microsaccades, as well as the need for improved methods to study small eye movements recorded with video-based eye trackers., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In this eye-tracking and drawing study, we investigate the perceptual grounding of different types of spatial dimensions such as dense-sparse and top-bottom, focusing both on the participants' experiences of the opposite regions, e.g., O1: dense; O2: sparse, and the region that is experienced as intermediate, e.g., INT: neither dense nor sparse. Six spatial dimensions expected to have three different perceptual structures in terms of the point and range nature of O1, INT and O2 were analysed. Presented with images, the participants were instructed to identify each region (O1, INT, O2), first by looking at the region, and then circumscribing it using the computer mouse. We measured the eye movements, identification times and various characteristics of the drawings such as the relative size of the three regions, overlaps and gaps. Three main results emerged. Firstly, generally speaking, intermediate regions were not different from the poles on any of the indicators: overall identification times, number of fixations, and locations. Some differences emerged with regard to the duration of fixations for point INTs and the number of fixations for range INTs between two range poles (O1, O2). Secondly, the analyses of the fixation locations showed that the poles support the identification of the intermediate region as much as the intermediate region supports the identification of the poles. Finally, the relative size of the three areas selected in the drawing task were consistent with the classification of the regions as points or ranges. The analyses of the gaps and the overlaps between the three areas showed that the intermediate is neither O1 nor O2, but an entity in its own right., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Dendritic cell (DC) vaccines have been demonstrated to elicit immunological responses in numerous cancer immunotherapy trials. However, long-lasting clinical effects are infrequent. We therefore sought to establish a protocol to generate DC with greater immunostimulatory capacity. Immature DC were generated from healthy donor monocytes by culturing in the presence of IL-4 and GM-CSF and were further differentiated into mature DC by the addition of cocktails containing different cytokines and toll-like receptor (TLR) agonists. Overall, addition of IFNγ and the TLR7/8 agonist R848 during maturation was essential for the production of high levels of IL-12p70 which was further augmented by adding the TLR3 agonist poly I:C. In addition, the DC matured with IFNγ, R848, and poly I:C also induced upregulation of several other pro-inflammatory and Th1-skewing cytokines/chemokines, co-stimulatory receptors, and the chemokine receptor CCR7. For most cytokines and chemokines the production was even further potentiated by addition of the TLR4 agonist LPS. Concurrently, upregulation of the anti-inflammatory cytokine IL-10 was modest. Most importantly, DC matured with IFNγ, R848, and poly I:C had the ability to activate IFNγ production in allogeneic T cells and this was further enhanced by adding LPS to the cocktail. Furthermore, epitope-specific stimulation of TCR-transduced T cells by peptide- or whole tumor lysate-loaded DC was efficiently stimulated only by DC matured in the full maturation cocktail containing IFNγ and the three TLR ligands R848, poly I:C, and LPS. We suggest that this cocktail is used for future clinical trials of anti-cancer DC vaccines.

Technological advancements in combination with significant reductions in price have made it practically feasible to run experiments with multiple eye trackers. This enables new types of experiments with simultaneous recordings of eye movement data from several participants, which is of interest for researchers in, e.g., social and educational psychology. The Lund University Humanities Laboratory recently acquired 25 remote eye trackers, which are connected over a local wireless network. As a first step toward running experiments with this setup, demanding situations with real time sharing of gaze data were investigated in terms of network performance as well as clock and screen synchronization. Results show that data can be shared with a sufficiently low packet loss (0.1 %) and latency (M = 3 ms, M A D = 2 ms) across 8 eye trackers at a rate of 60 Hz. For a similar performance using 24 computers, the send rate needs to be reduced to 20 Hz. To help researchers conduct similar measurements on their own multi-eye-tracker setup, open source software written in Python and PsychoPy are provided. Part of the software contains a minimal working example to help researchers kick-start experiments with two or more eye trackers.

Western-style diets (WD) high in fat and scarce in fiber and vitamin D increase risks of colorectal cancer. Here, we performed a long-term diet study in mice to follow tumorigenesis and characterize structural and metabolic changes in colon mucosa associated with WD and predisposition to colorectal cancer. WD increased colon tumor numbers, and mucosa proteomic analysis indicated severe deregulation of intracellular bile acid (BA) homeostasis and activation of cell proliferation. WD also increased crypt depth and colon cell proliferation. Despite increased luminal BA, colonocytes from WD-fed mice exhibited decreased expression of the BA transporters FABP6, OSTβ, and ASBT and decreased concentrations of secondary BA deoxycholic acid and lithocholic acid, indicating reduced activity of the nuclear BA receptor FXR. Overall, our results suggest that WD increases cancer risk by FXR inactivation, leading to BA deregulation and increased colon cell proliferation. Cancer Res; 77(12); 3352-63. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Objective: The aim of this study is to obtain a deeper understanding of midwives' lived experiences of caring for new mothers with initial breastfeeding difficulties., Methods: A reflective lifeworld approach was used. Six midwives were recruited from a hospital in western Sweden. Data were collected via individual lifeworld interviews and analysed using phenomenological methods., Results: The essential meaning can be described as a midwife's wish to help new mothers reach their breastfeeding goals by trying to interact with them as individual women in unique breastfeeding situations. This wish constitutes a contradiction to the midwife's own desire to succeed in enabling mothers to breastfeed and the perceived risk of failure as a midwife if the mothers decide not to breastfeed. This is further described by five constituents: striving to provide individualised care, collegial and personal responsibility both enables and prevents care, a struggle to be sufficient, an uphill struggle and mutual joy becomes the motivation to care., Conclusions: Caring for new mothers with initial breastfeeding difficulties is a balancing act between the midwife's personal desire to succeed in enabling mothers to breastfeed, the mothers' wishes, the infants' needs, the importance of collective collegial competence and the limitations in the health care organisation. This makes the midwife's efforts to provide individualised care frustrating and demanding as well as motivating., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Almost all eye-movement researchers use algorithms to parse raw data and detect distinct types of eye movement events, such as fixations, saccades, and pursuit, and then base their results on these. Surprisingly, these algorithms are rarely evaluated. We evaluated the classifications of ten eye-movement event detection algorithms, on data from an SMI HiSpeed 1250 system, and compared them to manual ratings of two human experts. The evaluation focused on fixations, saccades, and post-saccadic oscillations. The evaluation used both event duration parameters, and sample-by-sample comparisons to rank the algorithms. The resulting event durations varied substantially as a function of what algorithm was used. This evaluation differed from previous evaluations by considering a relatively large set of algorithms, multiple events, and data from both static and dynamic stimuli. The main conclusion is that current detectors of only fixations and saccades work reasonably well for static stimuli, but barely better than chance for dynamic stimuli. Differing results across evaluation methods make it difficult to select one winner for fixation detection. For saccade detection, however, the algorithm by Larsson, Nyström and Stridh (IEEE Transaction on Biomedical Engineering, 60(9):2484-2493,2013) outperforms all algorithms in data from both static and dynamic stimuli. The data also show how improperly selected algorithms applied to dynamic data misestimate fixation and saccade properties.

Ipilimumab has revolutionized malignant melanoma therapy, but a better understanding of the mechanisms behind treatment response and adverse effects is needed. In this work, the immune system of ipilimumab treated patients was monitored to investigate potential mechanisms of action that may correlate with treatment outcome. Blood samples from 43 advanced melanoma patients were taken before, during and at the end of treatment. Hematological parameters were measured and flow cytometry analysis was performed in fresh samples within two hours of sample collection. Strong differences in markers CD45RA, CCR7, HLA-DR and CD15 between fresh and cryopreserved samples were observed. Ipilimumab treatment increased absolute lymphocyte counts, eosinophils, effector T cells and their activation status, whilst diminishing the suppressive side of the immune response, acting on regulatory T cells and myeloid derived suppressor cells (MDSCs). These effects were visible after one ipilimumab infusion and, regarding eosinophil counts, correlated with onset of adverse events. Monocytic MDSCs were decreased in response to treatment only in patients with clinical benefit; additionally, patients with a lower frequency of these cells after the first ipilimumab infusion experienced increased overall survival. CD8 effector memory T cell frequencies at the end of treatment were higher in patients with clinical benefit and positively correlated with survival. These data show that a clinical response to ipilimumab not only requires reshaping T cell populations, but additionally involves a reduction in suppressive cells such as monocytic MDSCs. Our work could provide insight on predicting treatment outcome, assisting clinicians in offering the best personalized therapeutic approach.

This study analyses the effect of pictures in reading materials on the viewing patterns of dyslexic adults. By analysing viewing patterns using eye-tracking, we captured differences in eye movements between young adults with dyslexia and controls based on the influence of reading skill as a continuous variable of the total sample. Both types of participants were assigned randomly to view either text-only or a text + picture stimuli. The results show that the controls made an early global overview of the material and (when a picture was present) rapid transitions between text and picture. Having text illustrated with a picture decreased scores on questions about the learning material among participants with dyslexia. Controls spent 1.7% and dyslexic participants 1% of their time on the picture. Controls had 24% fewer total fixations; however, 29% more of the control group's fixations than the dyslexic group's fixations were on the picture. We also looked for effects of different types of pictures. Dyslexic subjects exhibited a comparable viewing pattern to controls when scenes were complex, but fewer fixations when scenes were neutral/simple. Individual scan paths are presented as examples of atypical viewing patterns for individuals with dyslexia as compared with controls. © 2016 The Authors. Dyslexia published by John Wiley & Sons Ltd., (© 2016 The Authors. Dyslexia published by John Wiley & Sons Ltd.)

Western-type diet (WD) is a risk factor for colorectal cancer, but the underlying mechanisms are poorly understood. We investigated the interaction of WD and heterozygous mutation in the Apc gene on adenoma formation and metabolic and immunological changes in the histologically normal intestinal mucosa of Apc Min/+ (Min/+) mice. The diet used was high in saturated fat and low in calcium, vitamin D, fiber and folate. The number of adenomas was twofold higher in the WD mice compared to controls, but adenoma size, proliferation or apoptosis did not differ. The ratio of the Min to wild-type allele was higher in the WD mice, indicating accelerated loss of Apc heterozygosity (LOH). Densities of intraepithelial CD3ε + T lymphocytes and of mucosal FoxP3 + regulatory T cells were higher in the WD mice, implying inflammatory changes. Western blot analyses from the mucosa of the WD mice showed suppressed activation of the ERK and AKT pathways and a tendency for reduced activation of the mTOR pathway as measured in phosphoS6/S6 levels. The expression of pyruvate dehydrogenase kinase 4 was up-regulated in both mRNA and protein levels. Gene expression analyses showed changes in oxidation/reduction, fatty acid and monosaccharide metabolic pathways, tissue organization, cell fate and regulation of apoptosis. Together, our results suggest that the high-risk Western diet primes the intestine to tumorigenesis through synergistic effects in energy metabolism, inflammation and oxidative stress, which culminate in the acceleration of LOH of the Apc gene., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Pathogenicity assessment of DNA variants in disease genes to explain their clinical consequences is an integral component of diagnostic molecular testing. The International Society for Gastrointestinal Hereditary Tumors (InSiGHT) has developed specific criteria for the interpretation of mismatch repair (MMR) gene variants. Here, we performed a systematic investigation of 24 MLH1 and MSH2 variants. The assessments were done by analyzing population frequency, segregation, tumor molecular characteristics, RNA effects, protein expression levels, and in vitro MMR activity. Classifications were confirmed for 15 variants and changed for three, and for the first time determined for six novel variants. Overall, based on our results, we propose the introduction of some refinements to the InSiGHT classification rules. The proposed changes have the advantage of homogenizing the InSIGHT interpretation criteria with those set out by the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium for the BRCA1/BRCA2 genes. We also observed that the addition of only few clinical data was sufficient to obtain a more stable classification for variants considered as "likely pathogenic" or "likely nonpathogenic." This shows the importance of obtaining as many as possible points of evidence for variant interpretation, especially from the clinical setting., (© 2016 WILEY PERIODICALS, INC.)

DNA repair mechanisms maintain genome stability by preventing the multiplication of genetic errors, caused by environmental factors and intracellular processes, during cell division. Unrepaired damage may permanently alter genome and cell functions, and even minor changes in DNA strand may initiate malignant transformation of the cell. Up to 25 000 changes in DNA are occur daily in a single, actively dividing, cell, and these changes are continuously repaired. If DNA repair mechanisms are impaired, errors will accumulate into the genome. As numerous factors of different nature can cause genetic errors, and thus several different DNA repair mechanisms are necessary to ensure genomic stability.

In a world of increasing interconnections in global trade as well as rapid change in climate and land cover, the accelerating introduction and spread of invasive species is a critical concern due to associated negative social and ecological impacts, both real and perceived. Much of the societal response to invasive species to date has been associated with negative economic consequences of invasions. This response has shaped a war-like approach to addressing invasions, one with an agenda of eradications and intense ecological restoration efforts towards prior or more desirable ecological regimes. This trajectory often ignores the concept of ecological resilience and associated approaches of resilience-based governance. We argue that the relationship between ecological resilience and invasive species has been understudied to the detriment of attempts to govern invasions, and that most management actions fail, primarily because they do not incorporate adaptive, learning-based approaches. Invasive species can decrease resilience by reducing the biodiversity that underpins ecological functions and processes, making ecosystems more prone to regime shifts. However, invasions do not always result in a shift to an alternative regime; invasions can also increase resilience by introducing novelty, replacing lost ecological functions or adding redundancy that strengthens already existing structures and processes in an ecosystem. This paper examines the potential impacts of species invasions on the resilience of ecosystems and suggests that resilience-based approaches can inform policy by linking the governance of biological invasions to the negotiation of tradeoffs between ecosystem services., (Copyright © 2016. Published by Elsevier Ltd.)

An increasing number of researchers record binocular eye-tracking signals from participants viewing moving stimuli, but the majority of event-detection algorithms are monocular and do not consider smooth pursuit movements. The purposes of the present study are to develop an algorithm that discriminates between fixations and smooth pursuit movements in binocular eye-tracking signals and to evaluate its performance using an automated video-based strategy. The proposed algorithm uses a clustering approach that takes both spatial and temporal aspects of the binocular eye-tracking signal into account, and is evaluated using a novel video-based evaluation strategy based on automatically detected moving objects in the video stimuli. The binocular algorithm detects 98% of fixations in image stimuli compared to 95% when only one eye is used, while for video stimuli, both the binocular and monocular algorithms detect around 40% of smooth pursuit movements. The present article shows that using binocular information for discrimination of fixations and smooth pursuit movements is advantageous in static stimuli, without impairing the algorithm's ability to detect smooth pursuit movements in video and moving-dot stimuli. With an automated evaluation strategy, time-consuming manual annotations are avoided and a larger amount of data can be used in the evaluation process.

Background: The complexity of analyzing eye-tracking signals increases as eye-trackers become more mobile. The signals from a mobile eye-tracker are recorded in relation to the head coordinate system and when the head and body move, the recorded eye-tracking signal is influenced by these movements, which render the subsequent event detection difficult., New Method: The purpose of the present paper is to develop a method that performs robust event detection in signals recorded using a mobile eye-tracker. The proposed method performs compensation of head movements recorded using an inertial measurement unit and employs a multi-modal event detection algorithm. The event detection algorithm is based on the head compensated eye-tracking signal combined with information about detected objects extracted from the scene camera of the mobile eye-tracker., Results: The method is evaluated when participants are seated 2.6m in front of a big screen, and is therefore only valid for distant targets. The proposed method for head compensation decreases the standard deviation during intervals of fixations from 8° to 3.3° for eye-tracking signals recorded during large head movements., Comparison With Existing Methods: The multi-modal event detection algorithm outperforms both an existing algorithm (I-VDT) and the built-in-algorithm of the mobile eye-tracker with an average balanced accuracy, calculated over all types of eye movements, of 0.90, compared to 0.85 and 0.75, respectively for the compared algorithms., Conclusions: The proposed event detector that combines head movement compensation and information regarding detected objects in the scene video enables for improved classification of events in mobile eye-tracking data., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Needle-related medical procedures (NRMPs) are something that all young children need to undergo at some point. These procedures may involve feelings of fear, pain and anxiety, which can cause problems later in life either when seeking healthcare in general or when seeking care specifically involving needles. More knowledge is needed about supporting children during these procedures., Aim: This study aims to explain and understand the meaning of the research phenomenon: support during NRMPs. The lived experiences of the phenomenon are interpreted from the perspective of younger children., Method: The analysis uses a lifeworld hermeneutic approach based on participant observations and interviews with children between 3 and 7years of age who have experienced NRMPs., Results: The research phenomenon, support for younger children during NRMPs, is understood through the following themes: being the centre of attention, getting help with distractions, being pampered, becoming involved, entrusting oneself to the safety of adults and being rewarded. A comprehensive understanding is presented wherein younger children experience support from adults during NRMPs in order to establish resources and/or strengthen existing resources., Conclusions: The manner in which the child will be guided through the procedure is developed based on the child's reactions. This approach demonstrates that children are actively participating during NRMPs. Supporting younger children during NRMPs consists of guiding them through a shared situation that is mutually beneficial to the child, the parent and the nurse. Play during NRMP is an important tool that enables the support to be perceived as positive., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Most modern video eye trackers use the p-CR (pupil minus CR) technique to deal with small relative movements between the eye tracker camera and the eye. We question whether the p-CR technique is appropriate to investigate saccade dynamics. In two experiments we investigated the dynamics of pupil, CR and gaze signals obtained from a standard SMI Hi-Speed eye tracker. We found many differences between the pupil and the CR signals. Differences concern timing of the saccade onset, saccade peak velocity and post-saccadic oscillation (PSO). We also obtained that pupil peak velocities were higher than CR peak velocities. Saccades in the eye trackers' gaze signal (that is constructed from p-CR) appear to be excessive versions of saccades in the pupil signal. We conclude that the pupil-CR technique is not suitable for studying detailed dynamics of eye movements., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Transitional object (TO) use is suggested to be related with various health problems. Prolonged TO use in adolescence is quite common, and research on its associations with health and psychosocial wellbeing is relevant because it does not necessarily represent pathologies in this age group., Aims: To investigate the role of transitional phenomena and attachment to an inanimate object in adolescence, possible explanatory variables were studied, including sociodemographic and psychosocial factors and self-image., Methods: The study group consisted of 992 subjects (433 boys and 559 girls), mean age 14.5 years (SD = 0.5), who were studying at comprehensive schools in the City of Turku, Finland. Information about the TO use and background data were collected with a semi-structured questionnaire. Mental distress and self-esteem were assessed by the Offer Self-Image Questionnaire (OSIQ)., Results: The multivariable logistic regression analysis revealed that, in the whole study group, significant explanatory factors for the TO use included female gender (p < 0.0001), frequent pain and aches (p = 0.008), and, of the OSIQ sub-scales, low Emotional Health (p = 0.006). For girls, significant explanatory factors for the TO use were pain and aches (p = 0.003) and low Emotional Health (p = 0.002). For boys, the only statistically significant explanatory factor was pain and aches (p = 0.02)., Conclusions: The TO may serve as a soothing element for somatoform pain symptoms in adolescence. Identifying of the TO use may help one see an adolescent's possible distress, symptoms of pains, and problems in psychological resilience.

While it is known that scleral search coils-measuring the rotation of the eye globe--and modern, video based eye trackers-tracking the center of the pupil and the corneal reflection (CR)--produce signals with different properties, the mechanisms behind the differences are less investigated. We measure how the size of the pupil affects the eye-tracker signal recorded during saccades with a common pupil-CR eye-tracker. Eye movements were collected from four healthy participants and one person with an aphakic eye while performing self-paced, horizontal saccades at different levels of screen luminance and hence pupil size. Results show that pupil-, and gaze-signals, but not the CR-signal, are affected by the size of the pupil; changes in saccade peak velocities in the gaze signal of more than 30% were found. It is important to be aware of this pupil size dependent change when comparing fine grained oculomotor behavior across participants and conditions., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Unlabelled: Needle-related medical procedures (NRMPs) are often frightening and cause children anxiety and pain. Only a few studies have examined the perspectives of younger children. More knowledge is needed about younger children's experiences in caring situations such as NRMPs., Aim: The aim of this study was to explain and understand the consequences related to NRMPs from younger children's perspectives., Methods: Participant observations and interviews with younger children who had experienced NRMPs were analysed using a lifeworld hermeneutic approach., Results: Experiencing fear is central for younger children during an NRMP and interpretation of its consequences formed the basis for the following themes: seeking security, realizing the adult's power, struggling for control, feeling ashamed, and surrendering. A comprehensive understanding is presented wherein younger children's experiences of NRMPs vary across time and space related to weakening and strengthening their feelings of fear., Conclusions: Awareness is needed that adults' power becomes more obvious for children during an NRMP. Children's surrender does not necessarily imply acceptance of the procedure. Providing children with opportunities to control elements of the procedure creates a foundation for active participation, and vice versa., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The reported size of microsaccades is considerably larger today compared to the initial era of microsaccade studies during the 1950s and 1960s. We investigate whether this increase in size is related to the fact that the eye-trackers of today measure different ocular structures than the older techniques, and that the movements of these structures may differ during a microsaccade. In addition, we explore the impact such differences have on subsequent analyzes of the eye-tracker signals. In Experiment I, the movement of the pupil as well as the first and fourth Purkinje reflections were extracted from series of eye images recorded during a fixation task. Results show that the different ocular structures produce different microsaccade signatures. In Experiment II, we found that microsaccade amplitudes computed with a common detection algorithm were larger compared to those reported by two human experts. The main reason was that the overshoots were not systematically detected by the algorithm and therefore not accurately accounted for. We conclude that one reason to why the reported size of microsaccades has increased is due to the larger overshoots produced by the modern pupil-based eye-trackers compared to the systems used in the classical studies, in combination with the lack of a systematic algorithmic treatment of the overshoot. We hope that awareness of these discrepancies in microsaccade dynamics across eye structures will lead to more generally accepted definitions of microsaccades., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Evidence has come to play a central role in health policymaking. However, policymakers tend to use other types of information besides research evidence. Most prior studies on evidence-informed policy have focused on the policy formulation phase without a systematic analysis of its implementation. It has been suggested that in order to fully understand the policy process, the analysis should include both policy formulation and implementation. The purpose of the study was to explore and compare two policies aiming to improve health and social care in Sweden and to empirically test a new conceptual model for evidence-informed policy formulation and implementation., Methods: Two concurrent national policies were studied during the entire policy process using a longitudinal, comparative case study approach. Data was collected through interviews, observations, and documents. A Conceptual Model for Evidence-Informed Policy Formulation and Implementation was developed based on prior frameworks for evidence-informed policymaking and policy dissemination and implementation. The conceptual model was used to organize and analyze the data., Results: The policies differed regarding the use of evidence in the policy formulation and the extent to which the policy formulation and implementation phases overlapped. Similarities between the cases were an emphasis on capacity assessment, modified activities based on the assessment, and a highly active implementation approach relying on networks of stakeholders. The Conceptual Model for Evidence-Informed Policy Formulation and Implementation was empirically useful to organize the data., Conclusions: The policy actors' roles and functions were found to have a great influence on the choices of strategies and collaborators in all policy phases. The Conceptual Model for Evidence-Informed Policy Formulation and Implementation was found to be useful. However, it provided insufficient guidance for analyzing actors involved in the policy process, capacity-building strategies, and overlapping policy phases. A revised version of the model that includes these aspects is suggested.

During steady fixation, observers make small fixational saccades at a rate of around 1-2 per second. Presentation of a visual stimulus triggers a biphasic modulation in fixational saccade rate-an initial inhibition followed by a period of elevated rate and a subsequent return to baseline. Here we show that, during passive viewing, this rate signature is highly sensitive to small changes in stimulus contrast. By training a linear support vector machine to classify trials in which a stimulus is either present or absent, we directly compared the contrast sensitivity of fixational eye movements with individuals' psychophysical judgements. Classification accuracy closely matched psychophysical performance, and predicted individuals' threshold estimates with less bias and overall error than those obtained using specific features of the signature. Performance of the classifier was robust to changes in the training set (novel subjects and/or contrasts) and good prediction accuracy was obtained with a practicable number of trials. Our results indicate a tight coupling between the sensitivity of visual perceptual judgements and fixational eye control mechanisms. This raises the possibility that fixational saccades could provide a novel and objective means of estimating visual contrast sensitivity without the need for observers to make any explicit judgement., (© 2015 The Author(s).)

Background: Lynch syndrome (LS) is associated with germline mutations in DNA mismatch repair (MMR) genes. The first "hit" to inactivate one allele of the predisposing MMR gene is present in every cell, contributing to accelerated tumorigenesis. Less information is available of the nature, timing, and order of other molecular "hits" required for tumor development. To this end, MMR protein expression and coordinated promoter methylation were examined in colorectal specimens prospectively collected from LS mutation carriers (n = 55) during colonoscopy surveillance (10/2011-5/2013), supplemented with retrospective specimens., Results: Loss of MMR protein corresponding to the gene mutated in the germline increased with dysplasia, with frequency of 0 % in normal mucosa, 50-68 % in low-grade dysplasia adenomas, and 100 % in high-grade dysplasia adenomas and carcinomas. Promoter methylation as a putative "second hit" occurred in 1/56 (2 %) of tumors with silenced MMR protein. A general hypermethylation tendency was evaluated by two gene sets, eight CpG island methylator phenotype (CIMP) genes, and seven candidate tumor suppressor genes linked to colorectal carcinoma (CRC). Hypermethylation followed the same trend as MMR protein loss and was present in some low-grade dysplasia adenomas that still expressed MMR protein suggesting the absence of a "second hit." To assess prospectively collected normal mucosa for carcinogenic "fields," the specimen donors were stratified according to age at biopsy (50 years or below vs. above 50 years) and further according to the absence vs. presence of a (previous or concurrent) diagnosis of CRC. In mutation carriers over 50 years old, two markers from the candidate gene panel (SFRP1 and SLC5A8) revealed a significantly elevated average degree of methylation in individuals with CRC diagnosis vs. those without., Conclusions: Our findings emphasize the importance and early appearance of epigenetic alterations in LS-associated tumorigenesis. The results serve early detection and assessment of progression of CRC.

Recent research has shown that the pupil signal from video-based eye trackers contains post saccadic oscillations (PSOs). These reflect pupil motion relative to the limbus (Nyström, Hooge, & Holmqvist, 2013). More knowledge about video-based eye tracker signals is essential to allow comparison between the findings obtained from modern systems, and those of older eye tracking technologies (e.g. coils and measurement of the Dual Purkinje Image-DPI). We investigated PSOs in horizontal and vertical saccades of different sizes with two high quality video eye trackers. PSOs were very similar within observers, but not between observers. PSO amplitude decreased with increasing saccade size, and this effect was even stronger in vertical saccades; PSOs were almost absent in large vertical saccades. Based on this observation we conclude that the occurrence of PSOs is related to deceleration at the end of a saccade. That PSOs are saccade size dependent and idiosyncratic is a problem for algorithmic determination of saccade endings. Careful description of the eye tracker, its signal, and the procedure used to extract saccades is required to enable researchers to compare data from different eye trackers., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The majority of new mothers in Sweden initiate breastfeeding and many experience initial difficulties. This experience is an important cause of early breastfeeding cessation. To increase understanding, there is a need to explore the lived experiences of the decision to continue or cease breastfeeding. The aim of this study is therefore to explain and understand how this decision is influenced by the meaning of severe initial difficulties., Methods: A lifeworld hermeneutical approach was used for the study. The study was conducted in Sweden with eight mothers who experienced severe difficulties with initial breastfeeding. All except one were interviewed on two different occasions resulting in fifteen interviews. The interviews were conducted between 2010 and 2013., Results: Mothers who experience severe difficulties with initial breastfeeding feel both overtaken and violated not only by their own infants and their own bodies but also by their anger, expectations, loneliness and care from health professionals. These feelings of being overtaken and invaded provoke an existential crisis and place mothers at a turning point in which these feelings are compared and put in relation to one another in the negotiation of the decision to continue or cease breastfeeding. This decision thus depends on the possibility of feeling secure with the breastfeeding relationship. If insecurity dominates, this can, in severe cases, create a feeling of fear of breastfeeding that is so great that there is no alternative but to stop breastfeeding., Conclusions: Existential security in the breastfeeding relationship seems to be an underlying factor for confidence and therefore a necessary condition for continued breastfeeding when having severe initial breastfeeding difficulties. Unresolved feelings of insecurity may be a serious barrier to further breastfeeding that can result in a fear of breastfeeding. Such fear can force the mother to cease breastfeeding. This study highlights how women are situated in a complex cultural and biological context of breastfeeding that has existential consequences for them. An existential crisis forces mothers into a turning point for the breastfeeding decision. In the existential crisis, mothers' responsibility for the mother-infant relationship guides continuing or ceasing breastfeeding.

Background: Being critically ill with a hematological disease is a challenge, sometimes causing a need for support in the adjustment to the stressful life situation. By providing Web-based communication for support from a nurse, patients get access to an alternative and untraditional way to communicate their issues., Objective: The aim was to describe the meaning of using Web-based communication for support from a patient perspective., Methods: A comprehensive randomized pilot study (n = 30) was conducted, allowing 15 patients in the experimental group to have access to the Web-based communication, to evaluate feasibility. Of these 15 participants, 10 were interviewed, focusing on their experiences. An empirical hermeneutical approach was used and the interpretive analysis focused on the meanings., Results: Web-based communication for support means a space for patients to have their say, consolidation of a matter, an extended caring relationship, access to individual medical assessment, and an opportunity for emotional processing. The main interpretation indicates that the patient's influence on the communication strengthens according to the asynchronous, faceless, and written communication. The increased, and in some sense constant, access to an individual medical and caring assessment, in turn, implies a feeling of safety., Conclusion: Web-based communication for support seems to have the potential to enhance patients' participation on their own terms., Implications for Practice: To achieve the possible advantages of Web-based communication for support, nurses must acquire knowledge about caring writing. It requires respect for the patient and articulated accuracy and attention in the response given.

It is well known that the crystalline lens (henceforth lens) can oscillate (or 'wobble') relative to the eyeball at the end of saccades. Recent research has proposed that such wobbling of the lens is a source of post-saccadic oscillations (PSOs) seen in data recorded by eye trackers that estimate gaze direction from the location of the pupil. Since the size of the lens wobbles increases with accommodative effort, one would predict a similar increase of PSO-amplitude in data recorded with a pupil based eye tracker. In four experiments, we investigated the role of lens accommodation on PSOs in a video-based eye tracker. In Experiment 1, we replicated previous results showing that PSO-amplitudes increase at near viewing distances (large vergence angles), when the lens is highly accommodated. In Experiment 2a, we manipulated the accommodative state of the lens pharmacologically using eye drops at a fixed viewing distance and found, in contrast to Experiment 1, no significant difference in PSO-amplitude related to the accommodative state of the lens. Finally, in Experiment 2b, the effect of vergence angle was investigated by comparing PSO-amplitudes at near and far while maintaining a fixed lens accommodation. Despite the pharmacologically fixed degree of accommodation, PSO-amplitudes were systematically larger in the near condition. In summary, PSOs cannot exhaustively be explained by lens wobbles. Possible confounds related to pupil size and eye-camera angle are investigated in Experiments 3 and 4, and alternative mechanisms behind PSOs are probed in the discussion., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Cumulative pressures from global climate and ocean change combined with multiple regional and local-scale stressors pose fundamental challenges to coral reef managers worldwide. Understanding how cumulative stressors affect coral reef vulnerability is critical for successful reef conservation now and in the future. In this review, we present the case that strategically managing for increased ecological resilience (capacity for stress resistance and recovery) can reduce coral reef vulnerability (risk of net decline) up to a point. Specifically, we propose an operational framework for identifying effective management levers to enhance resilience and support management decisions that reduce reef vulnerability. Building on a system understanding of biological and ecological processes that drive resilience of coral reefs in different environmental and socio-economic settings, we present an Adaptive Resilience-Based management (ARBM) framework and suggest a set of guidelines for how and where resilience can be enhanced via management interventions. We argue that press-type stressors (pollution, sedimentation, overfishing, ocean warming and acidification) are key threats to coral reef resilience by affecting processes underpinning resistance and recovery, while pulse-type (acute) stressors (e.g. storms, bleaching events, crown-of-thorns starfish outbreaks) increase the demand for resilience. We apply the framework to a set of example problems for Caribbean and Indo-Pacific reefs. A combined strategy of active risk reduction and resilience support is needed, informed by key management objectives, knowledge of reef ecosystem processes and consideration of environmental and social drivers. As climate change and ocean acidification erode the resilience and increase the vulnerability of coral reefs globally, successful adaptive management of coral reefs will become increasingly difficult. Given limited resources, on-the-ground solutions are likely to focus increasingly on actions that support resilience at finer spatial scales, and that are tightly linked to ecosystem goods and services., (© 2014 John Wiley & Sons Ltd.)

The aim of the research was to verify that electrospraying of piroxicam yielded a new polymorphic form of this drug. In the experiments, piroxicam was dissolved in chloroform and the solution was atomised electrostatically. Subsequently, the charged droplets were neutralised and dried. The solid drug particles were collected and analysed by scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, high performance liquid chromatography, and infrared and Raman spectroscopy. The X-ray diffractogram measured for the electrosprayed piroxicam particles did not match with any of the known piroxicam crystal structures (Cambridge Crystallographic Data Centre). The variable temperature X-ray diffraction showed that the structure recrystallised completely into piroxicam polymorphic formI during heating. No degradation products or solvate removal was detected by high performance liquid chromatography and thermal analysis. The infrared and Raman spectra of the electrosprayed piroxicam were compared to those of formI, and some notable differences in the peak positions, shapes and intensities were detected. The results indicate that electrospraying leads to piroxicam crystallisation in a currently unknown polymorphic form., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: To investigate patients who called the emergency medical services (EMS) for primary healthcare (PHC) problems., Design: A retrospective and exploratory patient record study from an EMS perspective, comparing two groups: those who were potential candidates for PHC and those who were not. All data were gathered from EMS and hospital records., Settings: The study was completed at the EMS and five hospital areas in the western region of Sweden., Subjects: The patients (n = 3001) who called the EMS in 2011. Data were missing for 10%., Main Outcome Measures: The frequency and the clinical characteristics of the patients who called the EMS and were actually potential candidates for PHC., Results: Of a total of 2703 patients, a group of 426 (16%) were assessed as potential candidates for PHC and could thus be treated at a level of care other than the emergency department. Patients who were classified as suitable for PHC were found at all priority levels and within all symptom groups, but were younger and healthier than the other group., Conclusion: Numerous patients seeking help from the EMS do not end up at the most appropriate level in the healthcare system., Implications: In the EMS, guidelines are needed to enable pre-hospital emergency nurses to assess and triage patients to the most appropriate level of healthcare. Key points Patients calling the emergency medical services do not always end up at an appropriate level of healthcare. In total, 16% of patients were identified by the Swedish emergency medical services as potential candidates for primary healthcare. These patients were younger and healthier than those needing care at the emergency department. They were found at all priority levels and within all symptom groups.

Context: Electrospraying was used in drug particle production., Objective: The aim of the research was to evaluate the possibilities to produce drug particles with desired pharmaceutical properties by electrospraying. In particular, the effect of drying pressure on particle properties was studied., Materials and Methods: A poorly water soluble model drug (budesonide) was dissolved in chloroform, and the solution was atomized by electrospraying. Following this, the charged droplets were neutralized and dried in a drying chamber. The pressure in the drying chamber was varied. The dried particles were collected and analyzed., Results: The pressure reduction had a slight impact on particle size distribution. The particles produced in reduced pressure turned out to be notably more porous than the particles produced in atmospheric pressure. The pressure reduction also affects the degree of crystallinity of the product. The dissolution of the particles produced in reduced pressures was faster to a certain extent than that of the particles produced in atmospheric pressure., Discussion and Conclusions: A setup for electrospraying materials in a reduced pressure was presented. The pressure reduction had a notable impact on particle morphology. The possibilities to tailor the particle properties during electrospraying were studied.

Human epidemiological evidence and previous studies on mice have shown that Western-style diet (WD) may predispose gut mucosa to colorectal cancer (CRC). The mechanisms that mediate the effects of diet on tumorigenesis are largely unknown. To address putative cancer-predisposing events available for early detection, we quantitatively analyzed the proteome of histologically normal colon of a wild-type (Mlh1(+/+)) and an Mlh1(+/-) mouse after a long-term feeding experiment with WD and AIN-93G control diet. The Mlh1(+/-) mouse carries susceptibility to colon cancer analogous to a human CRC syndrome (Lynch syndrome). Remarkably, WD induced expression changes reflecting metabolic disturbances especially in the cancer-predisposed colon, while similar changes were not significant in the wild-type proteome. Overall, the detected changes constitute a complex interaction network of proteins involved in ATP synthesis coupled proton transport, oxidoreduction coenzyme and nicotinamide nucleotide metabolic processes, important in cell protection against reactive oxygen species toxicity. Of these proteins, selenium binding protein 1 and galectin-4, which directly interact with MutL homolog 1, are underlined in neoplastic processes, suggesting that sensitivity to WD is increased by an Mlh1 mutation. The significance of WD on CRC risk is highlighted by the fact that five out of six mice with neoplasias were fed with WD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Many mothers initiate breastfeeding, but some of these experience difficulties. This study has two aims in order to contribute to the development of optimal care for these mothers: firstly to explain and understand the existential meanings of one mother's severe initial breastfeeding difficulties and how these meanings affected her continued breastfeeding and secondly, to reflect on a method for applying lifeworld hermeneutics to research on complex breastfeeding phenomena. This is an approach that acknowledges and focuses on the concrete and lived existence and what it means for humans. Within this approach, humans are understood as whole human beings interacting in the world. The study was conducted using lifeworld interviews with Anna, focusing on meanings of her difficult lived experience of initial breastfeeding. The existential interpretation suggests that such an experience can evoke existential vulnerability, a vulnerability that becomes evident in shameful feelings, such as dislike of breastfeeding, aversion to the milk-producing body and anger towards the child. Anna continued breastfeeding as a way to rid herself of the shame, hoping to be confirmed as a good mother. Such an experience may have negative consequences for the mother-child relationship and it can create fear for future breastfeeding. This study concludes that carers should be aware of individual existential dimensions for breastfeeding mothers.

Several work models for care improvement have been developed in order to meet the requirement for evidence-based care. This study examines a work model for reflection, entitled the reflective team (RT). The main idea behind RTs is that caring skills exist among those who work closest to the patients. The team leader (RTL) encourages sustainable care improvement, rooted in research and proven experience, by using a lifeworld perspective to stimulate further reflection and a developmental process leading to research-based caring actions within the team. In order to maintain focus, it is important that the RTL has a clear idea of what sustainable care improvement means, and what the prerequisites are for such improvement. The aim of the present study is, therefore, to explore the prerequisites for improving sustainable care, seeking to answer how RTLs perceive these and use RTs for concrete planning. Nine RTLs were interviewed, and their statements were phenomenographically analysed. The analysis revealed three separate qualitative categories, which describe personal, interpersonal, and structural aspects of the prerequisites. In the discussion, these categories are compared with previous research on reflection, and the conclusion is reached that the optimal conditions for RTs to work, when focussed on sustainable care improvement, occur when the various aspects of the prerequisites are intertwined and become a natural part of the reflective work.

Adoptive transfer of in vitro-expanded tumor-infiltrating lymphocytes (TIL) has shown great clinical benefit in patients with malignant melanoma. TIL therapy itself has little side effects, but conditioning chemo- or radiotherapy and postinfusion interleukin 2 (IL-2) injections are associated with severe adverse advents. We reasoned that combining TIL infusion with dendritic cell (DC) vaccination could circumvent the need for conditioning and IL-2 support and thus represent a milder treatment approach. Eight patients with stage IV melanoma were enrolled in the MAT01 study, consisting of vaccination with autologous tumor-lysate-loaded DC, followed by TIL infusion. Six of eight patients were treated according to protocol, while one patient received only TIL and one only DC. Treatments were well tolerated with a single grade 3 adverse event. The small study size precludes analysis of clinical responses, though interestingly one patient showed a complete remission and two had stable disease. Analysis of the infusion products revealed that mature DC were generated in all cases. TIL after expansion were CD3+ T cells, dominated by effector memory CD8+ cytotoxic T cells. Analysis of the T cell receptor repertoire revealed presence of highly dominant clones in most infusion products, and many of these could be detected in the circulation for weeks after T cell transfer. Here, we report the first combination of DC vaccination and TIL infusion in malignant melanoma. This combined treatment was safe and feasible, though after evaluating both clinical and immunological parameters, we expect that administration of lymphodepleting chemotherapy and IL-2 will likely increase treatment efficacy.

Lynch syndrome (LS), the most common familial colon cancer, is associated with mismatch repair (MMR) malfunction. As mutation carriers inherit one normal and one defected MMR gene allele, cancer risk can be considered as limited amount of normal MMR gene product. How reductions in different MMR gene expressions affect MMR capability is, however, not known. The in vitro MMR assay is a method for the pathogenicity assessment of MMR gene variants causing functional or expressional defects and thus also suitable to evaluate the effects of reduced expression of normal mRNA. Here, the assay was applied to quantify repair efficiencies of human cells retaining varying expression levels (25%/50%/75%) of the main LS susceptibility genes MLH1, MSH2, or MSH6. Compared with the shRNA knockdown control, already a 50% reduction in mRNA levels could be detected as decreased MMR function although without statistical significance in MLH1. In MSH2 and MLH1, total loss of MMR was achieved with 25% expression, whereas in MSH6 and MSH2, the repair capability decreased significantly already with 75% expression. Our results provide a preliminary indication of relative expressions required for wild-type function and suggest that the in vitro MMR assay could be used to recognize expression levels indicative of LS., (© 2014 WILEY PERIODICALS, INC.)

Ecological structures and processes occur at specific spatiotemporal scales, and interactions that occur across multiple scales mediate scale-specific (e.g., individual, community, local, or regional) responses to disturbance. Despite the importance of scale, explicitly incorporating a multi-scale perspective into research and management actions remains a challenge. The discontinuity hypothesis provides a fertile avenue for addressing this problem by linking measureable proxies to inherent scales of structure within ecosystems. Here we outline the conceptual framework underlying discontinuities and review the evidence supporting the discontinuity hypothesis in ecological systems. Next we explore the utility of this approach for understanding cross-scale patterns and the organization of ecosystems by describing recent advances for examining nonlinear responses to disturbance and phenomena such as extinctions, invasions, and resilience. To stimulate new research, we present methods for performing discontinuity analysis, detail outstanding knowledge gaps, and discuss potential approaches for addressing these gaps.

Background: Epidemiological data suggest a role for common viruses in the pathogenesis of multiple sclerosis (MS), and recent data showed a negative association of past cytomegalovirus (CMV) infection on pediatric MS risk., Objective: Our aim was to analyze the association of CMV infection with MS risk in an adult case-control material. A meta-analysis was performed to validate our findings., Methods: Epidemiological Investigation in MS (EIMS) is a case-control study with incident cases and population-based controls. Anti-CMV antibody titers were measured with ELISA, and HLA-A and DRB1 genotyping was performed with SSP-PCR, in 658 MS cases, who all fulfilled the McDonald criteria for MS, and 786 controls., Results: CMV seropositivity was associated with a decreased MS risk, OR = 0.73 (0.58-0.92 95% CI), p = 0.005, adjusted for index age, gender, smoking, sun exposure, EBNA1 IgG titer and HLA-A*02 and DRB1*15. When we removed all cases and controls younger than 18 years at index, the protective effect was still apparent., Conclusions: CMV is negatively associated with adult-onset MS pathology, consistent with results from a study on pediatric MS cases. It remains to be shown whether this negative association is due to a true protective effect of CMV infection on MS risk.

SNOMED CT is a compositional terminology. Construction of post-coordinated expressions allows users to specify new meaning by referencing existing SNOMED CT concepts. The use of post-coordinated expressions in information systems requires special software, a reasoner, to give the exact relations between post-coordinated expressions and existing SNOMED CT content. Thus, the performance characteristics of reasoners are important for implementation of post-coordination in information systems. This study aims to test how reasoners perform when a large number of post-coordinated expressions are added to SNOMED CT. The time needed to classify an ontology consisting of SNOMED CT plus an increasing number of post-coordinated expressions is measured. The best performing reasoner in this test classifies SNOMED CT plus 1 million post-coordinated expressions in 42 seconds. The time to classify grows a little less than quadratic as the size of the ontology increases. In conclusion, classification time is not a problem using current reasoners and current SNOMED CT releases even if a large number of post-coordinated expressions are added.

Current video eye trackers use information about the pupil center to estimate orientation and movement of the eye. While dual Purkinje eye trackers suffer from lens wobble and scleral search coils may be influenced by contact lens slippage directly after saccades, it is not known whether pupil-based eye trackers produces similar artifacts in the data. We recorded eye movements from participants making repetitive, horizontal saccades and compared the movement in the data with pupil- and iris movements extracted from the eye images. Results showed that post-saccadic instabilities clearly exist in data recorded with a pupil-based eye tracker. They also exhibit a high degree of reproducibility across saccades and within participants. While the recorded eye movement data correlated well with the movement of the pupil center, the iris center showed only little post-saccadic movement. This means that the pupil moves relative to the iris during post-saccadic eye movements, and that the eye movement data reflect pupil movement rather than eyeball rotation. Besides introducing inaccuracies and additional variability in the data, the pupil movement inside the eyeball influences the decision of when a saccade should end and the subsequent fixation should begin, and consequently higher order analyses based on fixations and saccades., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Colorectal cancer (CRC) is the second most common cause of cancer-related deaths in the Western world and interactions between genetic and environmental factors, including diet, are suggested to play a critical role in its etiology. We conducted a long-term feeding experiment in the mouse to address gene expression and methylation changes arising in histologically normal colonic mucosa as putative cancer-predisposing events available for early detection. The expression of 94 growth-regulatory genes previously linked to human CRC was studied at two time points (5 weeks and 12 months of age) in the heterozygote Mlh1(+/-) mice, an animal model for human Lynch syndrome (LS), and wild type Mlh1(+/+) littermates, fed by either Western-style (WD) or AIN-93G control diet. In mice fed with WD, proximal colon mucosa, the predominant site of cancer formation in LS, exhibited a significant expression decrease in tumor suppressor genes, Dkk1, Hoxd1, Slc5a8, and Socs1, the latter two only in the Mlh1(+/-) mice. Reduced mRNA expression was accompanied by increased promoter methylation of the respective genes. The strongest expression decrease (7.3 fold) together with a significant increase in its promoter methylation was seen in Dkk1, an antagonist of the canonical Wnt signaling pathway. Furthermore, the inactivation of Dkk1 seems to predispose to neoplasias in the proximal colon. This and the fact that Mlh1 which showed only modest methylation was still expressed in both Mlh1(+/-) and Mlh1(+/+) mice indicate that the expression decreases and the inactivation of Dkk1 in particular is a prominent early marker for colon oncogenesis.

Background: Fiducials can be used as surrogate for target position during radiotherapy. However, fiducial motion could lead to potential position errors when using fiducials in four-dimensional computed tomography (4DCT) treatment planning and for gated image guided radiotherapy (IGRT)., Material and Methods: One gold marker (GM) and 5, 10 and 15 mm nickel-titanium (NiTi) stents were inserted in a moving phantom for the purpose of fiducial detection in 4DCT and gated IGRT. Fiducial position errors in 4DCT and BrainLAB's gated IGRT were defined as residuals between fiducial detection and the actual physical position at the instance of image acquisition., Results: Fiducials position errors correlate to speed, fiducial type and orientation during 4DCT acquisition. Lower detection accuracy was measured for the 5 mm NiTi-stent relative to the 10 and 15 mm NiTi stents and GM. Fiducials with orientation 45° relative to the scan direction showed a lower detection accuracy relative to parallel and perpendicular orientations. The standard deviation of position errors in 4DCT were up to 2.2 mm with a maximum deviation of 4.0 mm. Using BrainLAB's gated IGRT the fiducials were detected with a standard deviation of 0.6 mm and a maximum deviation of 1.9 mm. For gated IGRT no correlation to fiducial speed was found., Conclusions: Clinical use of fiducials in combination with treatment planning on mid-ventilation CT phase for moving target should include margins up to 5.5 mm due to potential systematic position errors.

Purpose: The purpose of this study was to describe the prerequisites required for the provision and use of web-based communication for psychosocial support within a haematology clinic, from a patient and family perspective., Method: A qualitative design using content analysis was used. A strategically selected sample of patients (n = 11) and family members (n = 6) were offered access to a web-based communication capability with a nurse. After four months, individual interviews were conducted with all participants, in order to identify necessary prerequisites., Results: Preferences and characteristics of the individual patient or family member are crucial as to whether web-based communication for support is perceived as useful. To feel comfortable with writing and to self-identify the need for support are fundamental in getting motivated to use web-based communication. An effective organization around psychosocial support in general is another prerequisite. Goals and responsibilities must be clearly defined for patients and family members to understand their rights and enable the transformation of opportunities into practice. The use of web-based communication must also be a convenient and naturally incorporated part of both individual and organizational use of the web in general., Conclusions: Prerequisites of taking into account caretakers' different preferences and needs, providing highly structured psychosocial support activities and providing a congruent range of web services, are necessary for successful provision and use of web-based communication for psychosocial support., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The antibody reactivity against Epstein-Barr nuclear antigen-1 (EBNA-1), and 25-hydroxyvitamin D (25(OH)D) status have been associated with multiple sclerosis (MS) risk. Interaction between these two factors has been proposed., Objectives: The objective of this paper is to examine the association between antibody reactivity against EBNA-1 and five EBNA-1 domains, and the risk of MS, and to examine if these antibodies and 25(OH)D status interact regarding MS risk in prospectively collected blood samples., Methods: Antibody reactivity and 25(OH)D levels were measured using ELISAs in n = 192 MS cases and n = 384 matched controls. The risk of MS was analysed using matched logistic regression. Interaction on the additive scale was assessed., Results: The risk of MS increased across tertiles of antibody reactivity against EBNA-1, domain EBNA-1(402-502), and domain EBNA-1(385-420); p trends < 0.001. In young individuals (below median age at sampling, < 26.4 years), these associations were stronger, and 25(OH)D levels correlated inversely to antibody reactivity against EBNA-1 and the EBNA-1 domains. No statistical interaction was found., Conclusions: We confirm that increased antibody reactivity against EBNA-1 is a risk factor of MS. 25(OH)D status might influence the immune response towards Epstein-Barr virus in young subjects, and thereby modulate MS risk.

A novel algorithm for detection of saccades and postsaccadic oscillations in the presence of smooth pursuit movements is proposed. The method combines saccade detection in the acceleration domain with specialized on- and offset criteria for saccades and postsaccadic oscillations. The performance of the algorithm is evaluated by comparing the detection results to those of an existing velocity-based adaptive algorithm and a manually annotated database. The results show that there is a good agreement between the events detected by the proposed algorithm and those in the annotated database with Cohen's kappa around 0.8 for both a development and a test database. In conclusion, the proposed algorithm accurately detects saccades and postsaccadic oscillations as well as intervals of disturbances.

Blocking the immune checkpoint molecule CTL antigen-4 (CTLA-4) with ipilimumab has proven to induce long-lasting clinical responses in patients with metastatic melanoma. To study the early response that takes place after CTLA-4 blockade, peripheral blood immune monitoring was conducted in five patients undergoing ipilimumab treatment at baseline, three and nine weeks after administration of the first dose. Along with T-cell population analysis, this work was primarily focused on an in-depth study of the myeloid-derived suppressor cell (MDSC) populations. Ipilimumab treatment resulted in lower frequencies of regulatory T cells along with reduced expression levels of PD-1 at the nine-week time point. Three weeks after the initial ipilimumab dose, the frequency of granulocytic MDSCs was significantly reduced and was followed by a reduction in the frequency of arginase1-producing CD3(-) cells, indicating an indirect in trans effect that should be taken into account for future evaluations of ipilimumab mechanisms of action., (©2013 AACR.)