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Background Multiparametric MRI (mpMRI) became recognised in investigating those with suspected prostate cancer between 2010 and 2012; in the USA, the preventative task force moratorium on PSA screening was a strong catalyst. In a few short years, it has been adopted into daily urological and oncological practice. The pace of clinical uptake, born along by countless papers proclaiming high accuracy in detecting clinically significant prostate cancer, has sparked much debate about the timing of mpMRI within the traditional biopsy-driven clinical pathways. There are strongly held opposing views on using mpMRI as a triage test regarding the need for biopsy and/or guiding the biopsy pattern. Objective To review the evidence base and present a position paper on the role of mpMRI in the diagnosis and management of prostate cancer. Methods A subgroup of experts from the ESUR Prostate MRI Working Group conducted literature review and face to face and electronic exchanges to draw up a position statement. Results This paper considers diagnostic strategies for clinically significant prostate cancer; current national and international guidance; the impact of pre-biopsy mpMRI in detection of clinically significant and clinically insignificant neoplasms; the impact of pre-biopsy mpMRI on biopsy strategies and targeting; the notion of mpMRI within a wider risk evaluation on a patient by patient basis; the problems that beset mpMRI including inter-observer variability. Conclusions The paper concludes with a set of suggestions for using mpMRI to influence who to biopsy and who not to biopsy at diagnosis. Key Points • Adopt mpMRI as the first, and primary, investigation in the workup of men with suspected prostate cancer. • PI-RADS assessment categories 1 and 2 have a high negative predictive value in excluding significant disease, and systematic biopsy may be postponed, especially in men with low-risk of disease following additional risk stratification. • PI-RADS assessment category lesions 4 and 5 should be targeted; PI-RADS assessment category lesion 3 may be biopsied as a target, as part of systematic biopsies or may be observed depending on risk stratification. Electronic supplementary material The online version of this article (10.1007/s00330-019-06166-z) contains supplementary material, which is available to authorized users.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Swiss National Science Foundation OnBehalf Swiss-AF Investigators Background Atrial fibrillation (AF) is associated with loss of cognition and dementia. Cardiac autonomic dysfunction has been linked to cognitive decline. We aimed to investigate if reduced cardiac autonomic function (CAF) is associated with cognitive impairment in AF patients. Methods Patients with paroxysmal, persistent and permanent AF were enrolled from a multicenter cohort study if they presented in AF ("AF group") or in sinus rhythm ("SR group") on a baseline 5-minute ECG recording. Parameters quantifying CAF (heart rate variability triangular index (HRVI), mean heart rate (MHR), the root mean square of successive differences (RMSSD) and the standard deviation of the normal-to-normal intervals (SDNN)) were calculated. We used the Montreal Cognitive Assessment (MoCA) to assess global cognitive function. Results 1,685 AF patients with a mean age of 73 ± 8 years, 29% females, were included. The MoCA score was 24.5 ± 3.2 in the AF group (n = 710 patients) and 25.4 ± 3.2 in the SR group (n = 975 patients). After adjusting for multiple confounders, lower HRVI was associated with lower MoCA scores, both in the SR group (β=0.049; 95% confidence interval (CI): 0.016 to 0.081; p = 0.003) and in the AF group (β=0.068; 95% CI: 0.020 to 0.116; p = 0.006). In the AF group, higher MHR was associated with a poorer performance in the MoCA (β=-0.008; 95% CI: -0.014 to -0.002; p = 0.014 ). Other parameters of CAF were not associated with cognition. Conclusion Our data suggest that impaired CAF is associated with worse cognitive performance in patients with AF. Elderly AF patients with impaired HRVI might undergo cognitive testing in order to screen for cognitive impairment.

This study analyzes the relation between attention-deficit hyperactivity disorder (ADHD) and later-life labor market outcomes in the United States and whether these relationships are mediated by educational attainment. To overcome endogeneity concerns in the estimation of these relationships, we exploit the polygenic risk score (PRS) for ADHD in a cohort where the diagnosis of and treatment for ADHD were generally not available. We find that an increase in the PRS for ADHD reduces the likelihood of employment, individual income, and household wealth. Moreover, it increases the likelihood of receiving social security disability benefits, unemployment or worker compensation, and other governmental transfers. We provide evidence that educational attainment mediates these relationships to a considerable extent (14-58%).

Background We aimed to investigate the burden of informal care in Hungary (HU), Poland (PL) and Slovenia (SI). Methods A cross-sectional online survey was performed involving representative samples of 1000 respondents per country. Caregiving situations were explored; health status of informal caregivers/care recipients and care-related quality of life were assessed using the EQ-5D-5L and CarerQol-7D. Results The proportion of caregivers was (HU/PL/SI) 14.9, 15.0 and 9.6%, respectively. Their mean age was 56.1, 45.6 and 48.0, and the average time spent on informal care was 27.6, 35.5 and 28.8 h/week. Chronic care was dominant (> 1 year: 78.5%, 72.0%, 74.0%) and care recipients were mainly (own/in-law) parents. Average EQ-5D-5L scores of care recipients were 0.53, 0.49 and 0.52. For Poland and Slovenia, EQ-5D-5L scores of informal care providers were signifcantly lower than of other respondents. Average CarerQol-7D scores were (HU/PL/SI) 76.0, 69.6 and 70.9, and CarerQol-VAS was 6.8, 6.4 and 6.6, respectively. Overall, 89, 87, and 84% of caregivers felt some or a lot fulflment related to caring. Problems with combining tasks with daily activities were most important in Hungary and Slovenia. Women had a higher probability of being a caregiver in Hungary. CarerQol-7D scores were signifcantly associated with caregivers’ EQ-5D-5L scores. In Hungary and Poland, living in a larger household was positively, while caring for patients with mental health problems was negatively associated with CarerQol-7D scores. Conclusions These frst results from the Central and Eastern European region using preference-based measures for the evaluation of informal care can serve as a valuable input for health economic analyses.

T cells are considered pivotal in the pathology of multiple sclerosis (MS), but their function and antigen specificity are unknown. To unravel the role of T cells in MS pathology, we performed a comprehensive analysis on T cells recovered from paired blood, cerebrospinal fluid (CSF), normal-appearing white matter (NAWM) and white matter lesions (WML) from 27 MS patients with advanced disease shortly after death. The differentiation status of T cells in these compartments was determined by ex vivo flow cytometry and immunohistochemistry. T-cell reactivity in short-term T-cell lines (TCL), generated by non-specific stimulation of T cells recovered from the same compartments, was determined by intracellular cytokine flow cytometry. Central memory T cells predominated in CSF and effector memory T cells were enriched in NAWM and WML. WML-derived CD8+ T cells represent chronically activated T cells expressing a cytotoxic effector phenotype (CD95L and granzyme B) indicative for local antigenic stimulation (CD137). The same lesions also contained higher CD8+ T-cell frequencies expressing co-inhibitory (TIM3 and PD1) and co-stimulatory (ICOS) T-cell receptors, yet no evidence for T-cell senescence (CD57) was observed. The oligoclonal T-cell receptor (TCR) repertoire, particularly among CD8+ T cells, correlated between TCL generated from anatomically separated WML of the same MS patient, but not between paired NAWM and WML. Whereas no substantial T-cell reactivity was detected towards seven candidate human MS-associated autoantigens (cMSAg), brisk CD8+ T-cell reactivity was detected in multiple WML-derived TCL towards autologous Epstein–Barr virus (EBV) infected B cells (autoBLCL). In one MS patient, the T-cell response towards autoBLCL in paired intra-lesional TCL was dominated by TCRVβ2+CD8+ T cells, which were localized in the parenchyma of the respective tissues expressing a polarized TCR and CD8 expression suggesting immunological synapse formation in situ. Collectively, the data suggest the involvement of effector memory cytotoxic T cells recognizing antigens expressed by autoBLCL, but not the assayed human cMSAg, in WML of MS patients. Electronic supplementary material The online version of this article (doi:10.1007/s00401-017-1744-4) contains supplementary material, which is available to authorized users.

Background Hypermobility of the first carpometacarpal joint is mostly surgically treated with a volar approached stabilization by Eaton, but recent studies indicate the importance of the dorsoradial and intermetacarpal ligaments (DRL and IML) for carpometacarpal joint stability. The aim of this study was to compare a dorsal and volar technique for primary carpometacarpal hypermobility regarding pain and functional outcome. Methods Patients with non-degenerative, painful carpometacarpal hypermobility were included and were randomly assigned to either the volar technique using the FCR, or a dorsal technique using the ECRL. After premature termination of the trial, we followed all patients treated with the volar approach. Pain, strength, and ADL function using DASH and Michigan Hand Questionnaires (MHQ) were measured at baseline and 3 and 12 months after surgery. Results After including 16 patients, the randomized trial comparing the volar and dorsal technique was terminated because of significant increased pain in the dorsal group. Although none of the other outcome measures were significant in the underpowered comparison, in line with the pain scores, all variables showed a trend towards a worse outcome in the dorsal group. Between 2009 and 2012, 57 thumbs were surgically stabilized. We found significant better pain and MHQ scores, and after 1 year improved grip and key pinch strength. Patients returned to work within 8 (±7) weeks, of which 85 % in their original job. Conclusions Surgical stabilization of the thumb is an effective method for patients suffering from hypermobility regarding pain, daily function, and strength. We recommend a volar approach. Level of Evidence: Level I, therapeutic study

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment available. An increasing number of genetic causes of ALS are being identified, but how these genetic defects lead to motor neuron degeneration and to which extent they affect common cellular pathways remains incompletely understood. To address these questions, we performed an interactomic analysis to identify binding partners of wild-type (WT) and ALS-associated mutant versions of ATXN2, C9orf72, FUS, OPTN, TDP-43 and UBQLN2 in neuronal cells. This analysis identified several known but also many novel binding partners of these proteins. Interactomes of WT and mutant ALS proteins were very similar except for OPTN and UBQLN2, in which mutations caused loss or gain of protein interactions. Several of the identified interactomes showed a high degree of overlap: shared binding partners of ATXN2, FUS and TDP-43 had roles in RNA metabolism; OPTN- and UBQLN2-interacting proteins were related to protein degradation and protein transport, and C9orf72 interactors function in mitochondria. To confirm that this overlap is important for ALS pathogenesis, we studied fragile X mental retardation protein (FMRP), one of the common interactors of ATXN2, FUS and TDP-43, in more detail in in vitro and in vivo model systems for FUS ALS. FMRP localized to mutant FUS-containing aggregates in spinal motor neurons and bound endogenous FUS in a direct and RNA-sensitive manner. Furthermore, defects in synaptic FMRP mRNA target expression, neuromuscular junction integrity, and motor behavior caused by mutant FUS in zebrafish embryos, could be rescued by exogenous FMRP expression. Together, these results show that interactomics analysis can provide crucial insight into ALS disease mechanisms and they link FMRP to motor neuron dysfunction caused by FUS mutations. Electronic supplementary material The online version of this article (doi:10.1007/s00401-016-1575-8) contains supplementary material, which is available to authorized users.

Access to research papers has changed in the last decades: from printed to digital sources, from close to open access. Despite these changes and broader access to research results, there are still accessibility barriers. A very few number of conferences and journals state an accessibility policy of their publications in their websites. The production of accessible documents is not a common practice in conferences devoted to accessibility. Purpose: The purpose of this paper is to present the case study of DSAI 2016 (Software Development and Technologies for Enhancing Accessibility and Fighting Infoexclusion) conference, wherein we were in charge of making accessible its proceedings. Methods: We discuss the methods and technical procedures we carried out to turn the original articles in MS Word and Latex formats into accessible PDFs and the steps necessary in authoring, conversion and validation. Results: the papers of DSAI 2016 were published in accessible format after much effort, best tools and procedure were using MS Word plus PDF Axes plus PDF Accessibility checker. Conclusion: We state the need to include a new role in the organizing committee of conferences for dealing with accessible publishing.

Independent living technologies are fast gaining interest within both academia and industry, amid the realization that the world's population is ageing. Technology can increase the quality of life of older people, allowing them to age-in-place and helping them to remain physically, cognitively and socially engaged with their environment. However, little research in this area is applied. The paper argues for the necessity of moving such technology out of the research laboratory and into the home, where its real impact on the lives of older adults can be assessed. Moreover, a series of recommendations are outlined, encompassing the life cycle of independent living technologies, from ethnographic assessment, through to design, deployment and evaluation. This work is based on lessons learned in deploying such technologies to older people in over 200 homes. This paper can act as a guide for other researchers interested in developing technologies with older people.

In Panama City, the water supply sources for the population come mainly from surface waters, but in times of drought and extreme natural phenomena, the need to resort to underground sources is explored. This paper concerns an exploratory investigation with the aim of assessing the quality of groundwater in the southeastern part of the Province of Panama and to determine its possible use as drinking water during extreme natural phenomena. Monthly monitoring over a period of 15 months was carried out. The study included the sampling and analysis of groundwater by different physic-chemical, hydrochemical and biological parameters. The results showed that most of the parameters in the analysed groundwater conformed to the Panamanian drinking water norm and the water potability diagram, this is a convenient source of raw water for purification. As for other uses for this water source, it should be used with caution since it represents a medium risk of soil salinization for irrigation water; and it is a moderately hard water for industrial uses.

In this paper, we account for the direct and indirect effects of maternity leave entitlements on female labor force participation. We first explore theoretically the impact of maternity leave duration on female labor supply in the presence of fertility decisions. We assume that maternity leave duration affects female labor supply through two main channels: reducing the time cost of female market work, and reducing women’s earnings. Our theoretical model allows for non-monotonic effects of leave duration on female labor supply. We test the predictions of our model using an unbalanced panel of 159 countries for the years 1994, 2004, and 2011. We confirm the existence of an inverted U-shaped relationship between maternity leave duration and female participation, and find a maternity leave threshold of around 30 weeks above which female participation falls. Below this threshold, increasing maternity leave increases female labor force participation because the positive effect due to the reduction of work–time cost of employed mothers strongly dominates the negative wage penalty effect. Beyond this threshold, the opposite happens. Our analysis also confirms the relevance of social norms for female labor supply throughout the world.

In this paper, a semi-automatic approach for building a sentiment domain ontology is proposed. Differently than other methods, this research makes use of synsets in term extraction, concept formation, and concept subsumption. Using several state-of-the-art hybrid aspect-based sentiment analysis methods like Ont + CABASC and Ont + LCR-Rot-hop on a standard dataset, the accuracies obtained using the semi-automatically built ontology as compared to the manually built one, are slightly lower (from approximately 87% to 84%). However, the user time needed for building the ontology is reduced by more than half (from 7 h to 3 h), thus showing the usefulness of this work. This is particularly useful for domains for which sentiment ontologies are not yet available.

This paper investigates the factors associated with foreign direct investment “surges” and “stops”, defined as sharp increases and decreases, respectively, of foreign direct investment inflows to the developing world and differentiated based on whether these events are led by waves in greenfield investments or mergers and acquisitions. Greenfield-led surges and stops occur more frequently than mergers-and-acquisitions-led ones and different factors are associated with the onset of the two types of events. Global liquidity is the factor significantly and positively associated with a surge, regardless of its kind, while a global economic growth slowdown and a surge in the preceding year are the main factors associated with a stop. Greenfield-led surges and stops are more likely in low-income countries and mergers-and-acquisitions-led surges are less likely in resource-rich countries than elsewhere in the developing world. Global growth accelerations and increases in financial openness, domestic economic and financial instability are associated with mergers-and-acquisitions-led surges but not with greenfield-led ones. These results are particularly relevant for developing countries where FDI flows are the major type of capital flows and suggest that developing countries’ macroeconomic vulnerability increases following periods of increased global liquidity. As countries develop they typically become more exposed to merger-and-acquisition-led surges, which are more likely than greenfield-led surges and stops to be short-lived and associated with domestic macroeconomic policies.

In this paper, we propose an ansatz for defining Gopakumar–Vafa invariants of Calabi–Yau threefolds, using perverse sheaves of vanishing cycles. Our proposal is a modification of a recent approach of Kiem–Li, which is itself based on earlier ideas of Hosono–Saito–Takahashi. We conjecture that these invariants are equivalent to other curve-counting theories such as Gromov–Witten theory and Pandharipande–Thomas theory. Our main theorem is that, for local surfaces, our invariants agree with PT invariants for irreducible one-cycles. We also give a counter-example to the Kiem–Li conjectures, where our invariants match the predicted answer. Finally, we give examples where our invariant matches the expected answer in cases where the cycle is non-reduced, non-planar, or non-primitive., National Science Foundation (U.S.) (Grant DMS-1645082), National Science Foundation (U.S.) (Grant DMS-1564458)

In the original paper, Fig.4 contains the wrong label preliminary. The label has been fixed, while none of the results have changed.

Intracranial carotid artery calcification (ICAC) is a major risk factor for stroke, and might contribute to dementia and cognitive decline. Reliance on time-consuming manual annotation of ICAC hampers much demanded further research into the relationship between ICAC and neurological diseases. Automation of ICAC segmentation is therefore highly desirable, but difficult due to the proximity of the lesions to bony structures with a similar attenuation coefficient. In this paper, we propose a method for automatic segmentation of ICAC; the first to our knowledge. Our method is based on a 3D fully convolutional neural network that we extend with two regularization techniques. Firstly, we use deep supervision to encourage discriminative features in the hidden layers. Secondly, we augment the network with skip connections, as in the recently developed ResNet, and dropout layers, inserted in a way that skip connections circumvent them. We investigate the effect of skip connections and dropout. In addition, we propose a simple problem-specific modification of the network objective function that restricts the focus to the most important image regions and simplifies the optimization. We train and validate our model using 882 CT scans and test on 1,000. Our regularization techniques and objective improve the average Dice score by 7.1%, yielding an average Dice of 76.2% and 97.7% correlation between predicted ICAC volumes and manual annotations.

Augmenting X-ray imaging with 3D roadmap to improve guidance is a common strategy. Such approaches benefit from automated analysis of the X-ray images, such as the automatic detection and tracking of instruments. In this paper, we propose a real-time method to segment the catheter and guidewire in 2D X-ray fluoroscopic sequences. The method is based on deep convolutional neural networks. The network takes as input the current image and the three previous ones, and segments the catheter and guidewire in the current image. Subsequently, a centerline model of the catheter is constructed from the segmented image. A small set of annotated data combined with data augmentation is used to train the network. We trained the method on images from 182 X-ray sequences from 23 different interventions. On a testing set with images of 55 X-ray sequences from 5 other interventions, a median centerline distance error of 0.2 mm and a median tip distance error of 0.9 mm was obtained. The segmentation of the instruments in 2D X-ray sequences is performed in a real-time fully-automatic manner.

This paper presents multiple hybridizations of the two best bots on the BotPrize 2014 competition, which sought for the best humanlike bot playing the First Person Shooter game Unreal Tournament 2004. To this aim the participants were evaluated using a Turing test in the game. The work considers MirrorBot (the winner) and NizorBot (the second) codes and combines them in two different approaches, aiming to obtain a bot able to show the best behaviour overall. There is also an evolutionary version on MirrorBot, which has been optimized by means of a Genetic Algorithm. The new and the original bots have been tested in a new, open, and public Turing test whose results show that the evolutionary version of MirrorBot apparently improves the original bot, and also that one of the novel approaches gets a good humanness level. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech.

In this paper, we establish a link between the structure theory of the pro-unipotent motivic fundamental group of the projective line minus three points and Diophantine geometry. In particular, we give a p-adic proof of Siegel's theorem.

This paper presents a new method of reconstructing the individual charged and neutral hadrons in tau decays with the ATLAS detector. The reconstructed hadrons are used to classify the decay mode and to calculate the visible four-momentum of reconstructed tau candidates, significantly improving the resolution with respect to the calibration in the existing tau reconstruction. The performance of the reconstruction algorithm is optimised and evaluated using simulation and validated using samples of Z→ ττ and Z(→ μμ) +jets events selected from proton–proton collisions at a centre-of-mass energy √s=8TeV, corresponding to an integrated luminosity of 5 fb[superscript - 1]., National Science Foundation (U.S.), United States. Department of Energy

Dear Editor: With interest we read the paper ‘A minimum yield of twelve lymph nodes in rectal cancer remains valid in the era of neoadjuvant treatment’ by Lykke et al. published on 5 February 2015 [Epub ahead of print]. In this study, the authors found an association between increased lymph node yield and the detection of node positive disease up to a lymph node yield of 12 to 17 nodes for rectal cancer patients (irrespective of neoadjuvant treatment). They reason that this indicates that a yield of at least 12 lymph nodes is needed to ensure node negative disease, and that guidelines on a minimum yield of 12 lymph nodes are valid. Althoughwe agree with the authors that an adequate lymph node evaluation is important for correct staging and subsequent treatment of patients, we do not believe that their conclusion is justified that the adequacy of lymph node yield and staging can be determined on the basis of a certain minimum number of lymph nodes evaluated. In our opinion, certain important aspects were not taken into account in this study. In the last two decades, the number of lymph nodes evaluated has become a surrogate marker for surgical and pathological excellence in colorectal cancer. Quality initiatives aimed at improving nodal yield have been undertaken and have resulted in an increase in the number of lymph nodes evaluated over time, indicating that room for improvement in surgical and pathological practices existed. However, a ceiling may have been reached beyond which further improvement might not be possible. This can be explained by the fact that the number of lymph nodes available for evaluation is not only influenced by the thoroughness of the surgeon and the diligence of the pathologist but also by a patient’s ability to mount an effective immune response to the tumour. A growing body of literature (i.e. studies by Pages and Galon et al. in the New England Journal of Medicine, Science and Journal of Clinical Oncology) is showing that the biological behaviour of the tumour and host, such as immune response, also affects the number of traceable lymph nodes. A smaller number of lymph nodes reflects a diminished immune response and is also associated with less prominent lymphocytic infiltration into the primary tumour. Consequently, it may be unrealistic to only define a lymph node evaluation as adequate in case 12 or more lymph nodes are yielded. Additionally, other recent studies among colon and rectal cancer patients such as the study by Parsons et al. in the Journal of the American Medical Association in 2011 and the study by Van Erning et al. in European Journal of Cancer in 2014 show that despite increases in lymph node yield over time, the proportion of lymph node positivity has remained unchanged, which makes one question the presumed understaging mechanism. Therefore, we believe that adequacy of lymph node yield and staging in rectal cancer should not be determined based on a minimum number of lymph nodes evaluated. Surgeons and pathologists should strive to remove and evaluate all lymph nodes in the resection specimen, while acknowledging that fewer than 12 lymph nodes might be present in some patients. The absolute number of lymph nodes evaluated should not be used as a marker of quality but should rather be regarded as a reflection of immune response. F. N. van Erning (*) :V. E. P. P. Lemmens Department of Research, Netherlands Comprehensive Cancer Organisation (IKNL), Eindhoven, The Netherlands e-mail: f.vanerning@iknl.nl