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Musical training has long been viewed as a model for experience-dependent brain plasticity. Reports of musical training-induced brain plasticity are largely based on cross-sectional studies comparing musicians to non-musicians, which cannot address whether musical training itself is sufficient to induce these neurobiological changes or whether pre-existing neuroarchitecture before training predisposes children to succeed in music. Here, in a longitudinal investigation of children from infancy to school age (n = 25), we find brain structure in infancy that predicts subsequent music aptitude skills at school-age. Building on prior evidence implicating white matter organization of the corticospinal tract as a neural predisposition for musical training in adults, here we find that structural organization of the right corticospinal tract "in infancy" is associated with school-age tonal and rhythmic musical aptitude skills. Moreover, within the corpus callosum, an inter-hemispheric white matter pathway traditionally linked with musical training, we find that structural organization of this pathway in infancy is associated with subsequent tonal music aptitude. Our findings suggest predispositions prior to the onset of musical training from as early as infancy may serve as a scaffold upon which ongoing musical experience can build.

Dyslexia has frequently been related to atypical auditory temporal processing and speech perception. Results of studies emphasizing speech onset cues and reinforcing the temporal structure of the speech envelope, that is, envelope enhancement (EE), demonstrated reduced speech perception deficits in individuals with dyslexia. The use of this strategy as auditory intervention might thus reduce some of the deficits related to dyslexia. Importantly, reading-skill interventions are most effective when they are provided during kindergarten and first grade. Hence, we provided a tablet-based 12-week auditory and phonics-based intervention to pre-readers at cognitive risk for dyslexia and investigated the effect on auditory temporal processing with a rise time discrimination (RTD) task. Ninety-one pre-readers at cognitive risk for dyslexia (aged 5-6) were assigned to two groups receiving a phonics-based intervention and playing a story listening game either with (n = 31) or without (n = 31) EE or a third group playing control games and listening to non-enhanced stories (n = 29). RTD was measured directly before, directly after and 1 year after the intervention. While the groups listening to non-enhanced stories mainly improved after the intervention during first grade, the group listening to enhanced stories improved during the intervention in kindergarten and subsequently remained stable during first grade. Hence, an EE intervention improves auditory processing skills important for the development of phonological skills. This occurred before the onset of reading instruction, preceding the maturational improvement of these skills, hence potentially giving at risk children a head start when learning to read. A video abstract of this article can be viewed at https://www.youtube.com/watch?v=e0BfT4dGXNA

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung condition. Currently, care models predominantly focus on acute medical and pharmacological needs. As a step towards holistic care, the aim of this prospective study was to investigate the psychological and behavioural needs of IPF patients treated with pirfenidone from diagnosis until two years of follow-up. Methods The following variables were selected from the literature on patients’ needs and the COM-B model, a theoretical model explaining behaviour: medication adherence, barriers to adherence, importance and intentions of medication adherence, anxiety, depression, health literacy, knowledge, reported side effects, adherence to sun protection recommendations, alcohol use, physical activity, quality of life and health status. Linear and generalised linear models for longitudinal data were used to evaluate the evolution since treatment initiation. Results We included 66 outpatients: 72.7% men, mean age of 70.3 years (range 50–87), predicted mean forced vital capacity of 85.8% (SD 17.4) and predicted mean diffusing capacity for monoxide of 56.9% (SD 15.7). The participants placed considerable importance on following the treatment recommendations. We noticed difficulties regarding health literacy, alcohol use, pirfenidone adherence (decline over time) and adherence to sun protection recommendations (early in follow-up care). There were low levels of physical activity (no effect of time), high body mass indices (decline over time) and moderate levels of depression and anxiety. Conclusion When providing care to IPF patients, behavioural issues, health literacy and psychological well-being should be taken into consideration. There is a need to further explore interventions and care models to tackle these difficulties. Trial registration This study was registered in the ClinicalTrials.gov database (identifier NCT03567785) on May 9th, 2018

Research demonstrated that a dyslexia diagnosis is mainly given after the most effective time for intervention has passed, referred to as the dyslexia paradox. Although some pre-reading cognitive measures have been found to be strong predictors of early literacy acquisition, i.e., phonological awareness (PA), letter knowledge (LK), and rapid automatized naming (RAN), more insight in the variability of pre-reading profiles might be of great importance for early identification of children who have an elevated risk for developing dyslexia and to provide tailor-made interventions. To address this issue, this study used a latent profile analysis (LPA) to disentangle different pre-reading profiles in a sample of 1091 Dutch-speaking kindergartners. Four profiles emerged: high performers (16.50%), average performers (40.24%), below-average performers with average IQ (25.57%), and below-average performers with below-average IQ (17.69%). These results suggested two at-risk profiles diverging in IQ, which are presumably more likely to develop dyslexia later on. Although below-average profiles differed significantly in rapid naming and IQ, no clear evidence for the double-deficit theory was found in Dutch-speaking kindergartners. Educational level and reading history of the parents appeared to be predictive for children's classification membership. Our results point towards the heterogeneity that is already present in kindergartners and the possibility to identify at-risk profiles prior to reading instruction, which may be the foundation for earlier targeted interventions. However, more extended research is needed to determine the stability of these profiles across time and across different languages.

There is an ongoing debate whether phonological deficits in dyslexics should be attributed to (a) less specified representations of speech sounds, like suggested by studies in young children with a familial risk for dyslexia, or (b) to an impaired access to these phonemic representations, as suggested by studies in adults with dyslexia. These conflicting findings are rooted in between study differences in sample characteristics and/or testing techniques. The current study uses the same multivariate functional MRI (fMRI) approach as previously used in adults with dyslexia to investigate phonemic representations in 30 beginning readers with a familial risk and 24 beginning readers without a familial risk of dyslexia, of whom 20 were later retrospectively classified as dyslexic. Based on fMRI response patterns evoked by listening to different utterances of /bA/ and /dA/ sounds, multivoxel analyses indicate that the underlying activation patterns of the two phonemes were distinct in children with a low family risk but not in children with high family risk. However, no group differences were observed between children that were later classified as typical versus dyslexic readers, regardless of their family risk status, indicating that poor phonemic representations constitute a risk for dyslexia but are not sufficient to result in reading problems. We hypothesize that poor phonemic representations are trait (family risk) and not state (dyslexia) dependent, and that representational deficits only lead to reading difficulties when they are present in conjunction with other neuroanatomical or--functional deficits.

Developmental dyslexia is considered to be most effectively addressed with preventive phonics-based interventions, including grapheme-phoneme coupling and blending exercises. These intervention types require intact speech perception abilities, given their large focus on exercises with auditorily presented phonemes. Yet some children with (a risk for) dyslexia experience problems in this domain due to a poorer sensitivity to rise times, i.e., rhythmic acoustic cues present in the speech envelope. As a result, the often subtle speech perception problems could potentially constrain an optimal response to phonics-based interventions in at-risk children. The current study therefore aimed (1) to extend existing research by examining the presence of potential speech perception deficits in pre-readers at cognitive risk for dyslexia when compared to typically developing peers and (2) to explore the added value of a preventive auditory intervention for at-risk pre-readers, targeting rise time sensitivity, on speech perception and other reading-related skills. To obtain the first research objective, we longitudinally compared speech-in-noise perception between 28 5-year-old pre-readers with and 30 peers without a cognitive risk for dyslexia during the second half of the third year of kindergarten. The second research objective was addressed by exploring growth in speech perception and other reading-related skills in an independent sample of 62 at-risk 5-year-old pre-readers who all combined a 12-week preventive phonics-based intervention (GraphoGame-Flemish) with an auditory story listening intervention. In half of the sample, story recordings contained artificially enhanced rise times (GG-FL_EE group, n = 31), while in the other half, stories remained unprocessed (GG-FL_NE group, n = 31; Clinical Trial Number S60962—https://www.uzleuven.be/nl/clinical-trial-center). Results revealed a slower speech-in-noise perception growth in the at-risk compared to the non-at-risk group, due to an emerged deficit at the end of kindergarten. Concerning the auditory intervention effects, both intervention groups showed equal growth in speech-in-noise perception and other reading-related skills, suggesting no boost of envelope-enhanced story listening on top of the effect of combining GraphoGame-Flemish with listening to unprocessed stories. These findings thus provide evidence for a link between speech perception problems and dyslexia, yet do not support the potential of the auditory intervention in its current form.

Hoewel de meeste kinderen vlot leren lezen, is dit niet voor iedereen het geval. Sommige kinderen ontwikkelen dyslexie, gekenmerkt door ernstige en hardnekkige problemen bij het leren lezen die in de meeste gevallen persisteren door de tijd, tot op het niveau van gevorderde lezers. Het is bekend dat de groep van personen met dyslexie atypische afwijkingen vertoont in de hersenen ten opzichte van typische lezers. Het is echter nog niet bekend of deze verschillen het gevolg zijn van de belemmerde leesontwikkeling, of er juist aan de basis van liggen. Met het oog op vroege en geïndividualiseerde interventie, is het belangrijk om inzicht te verwerven in de oorzakelijke factoren van dyslexie. Daarom werden in het afgelopen decennium een aantal longitudinale studies uitgevoerd die startten voor aanvang van de leesontwikkeling en de leesontwikkeling volgden aan de hand van gedragsmetingen en metingen van neurale kenmerken van het leesnetwerk. Deze studies werden steeds uitgevoerd bij een groep van kinderen die een verhoogd risico op dyslexie vertoonden, bijvoorbeeld vanwege een familiale voorgeschiedenis van dyslexie, of van een cognitief risicoprofiel. In dit artikel gaan we verder in op de resultaten van deze studies; meer specifiek op de structurele neurale verbindingen van het leesnetwerk en op recente inzichten met betrekking tot de structurele plasticiteit van deze wittestofbanen als gevolg van specifieke leesinterventies. Deze studies bieden inzicht in de manier waarop interventies een impact kunnen hebben op de neurale leesprocessen en dit zowel voor beginnende als gevorderde lezers.

BackgroundEnjoyment plays a key role in the success and feasibility of serious gaming interventions. Unenjoyable games will not be played, and in the case of serious gaming, learning will not occur. Therefore, a so-called GameFlow model has been developed, which intends to guide (serious) game developers in the process of creating and evaluating enjoyment in digital (serious) games. Regarding language learning, a variety of serious games targeting specific language components exist in the market, albeit often without available assessments of enjoyment or feasibility. ObjectiveThis study evaluates the enjoyment and feasibility of a tablet-based, serious story-listening game for kindergarteners, developed based on the principles of the GameFlow model. This study also preliminarily explores the possibility of using the game to foster language comprehension. MethodsWithin the framework of a broader preventive reading intervention, 91 kindergarteners aged 5 years with a cognitive risk for dyslexia were asked to play the story game for 12 weeks, 6 days per week, either combined with a tablet-based phonics intervention or control games. The story game involved listening to and rating stories and responding to content-related questions. Game enjoyment was assessed through postintervention questionnaires, a GameFlow-based evaluation, and in-game story rating data. Feasibility was determined based on in-game general question response accuracy (QRA), reflecting the difficulty level, attrition rate, and final game exposure and training duration. Moreover, to investigate whether game enjoyment and difficulty influenced feasibility, final game exposure and training duration were predicted based on the in-game initial story ratings and initial QRA. Possible growth in language comprehension was explored by analyzing in-game QRA as a function of the game phase and baseline language skills. ResultsEventually, data from 82 participants were analyzed. The questionnaire and in-game data suggested an overall enjoyable game experience. However, the GameFlow-based evaluation implied room for game design improvement. The general QRA confirmed a well-adapted level of difficulty for the target sample. Moreover, despite the overall attrition rate of 39% (32/82), 90% (74/82) of the participants still completed 80% of the game, albeit with a large variation in training days. Higher initial QRA significantly increased game exposure (β=.35; P

Dyslexia is targeted most effectively when (1) interventions are provided preventively, before the onset of reading instruction, and (2) remediation programs combine letter-sound training with phoneme blending. Given the growing potential of technology in educational contexts, there has been a considerable increase of letter-sound trainings embedded in digital serious games. One such intervention is GraphoGame. Yet, current evidence on the preventive impact of GraphoGame is limited by the lack of adaptation of the original learning content to the skills of pre-readers, short training duration, and a restricted focus on explicitly trained skills. Therefore, the current study aims at investigating the impact of a preventive, and pre-reading adapted GraphoGame training (i.e., GraphoGame-Flemish, GG-FL) on explicitly trained skills and non-specifically trained phonological and language abilities. Following a large-scale screening (N = 1225), the current study included 88 pre-reading kindergarteners at cognitive risk for dyslexia who were assigned to three groups training either with GG-FL (n = 31), an active control game (n = 29), or no game (n = 28). Before and after the 12-week intervention, a variety of reading-related skills were assessed. Moreover, receptive letter knowledge and phonological awareness were measured every three weeks during the intervention period. Results revealed significantly larger improvements in the GG-FL group on explicitly trained skills, i.e., letter knowledge and word decoding, without finding transfer-effects to untrained phonological and language abilities. Our findings imply a GG-FL-driven head start on early literacy skills in at-risk children. A follow-up study should uncover the long-term impact and the ability of GG-FL to prevent actual reading failure.

Although the neural basis of dyslexia has intensively been investigated, results are still unclear about the existence of a white matter deficit in the arcuate fasciculus (AF) throughout development. To unravel this ambiguity, we examined the difference in fractional anisotropy (FA) of the AF between children developing dyslexia and children developing typical reading skills in a longitudinal sample with three MRI time points throughout reading development: the pre-reading stage (5–6 years old), the early reading stage (7–8 years old) and the advanced reading stage (9–10 years old). Applying along-the-tract analyses of white matter organization, our results confirmed that a white matter deficit existed in the left AF prior to the onset of formal reading instruction in children who developed dyslexia later on. This deficit was consistently present throughout the course of reading development. Additionally, we evaluated the use of applying a continuous approach on the participants’ reading skills rather than the arbitrary categorization in individuals with or without dyslexia. Our results confirmed the predictive relation between FA and word reading measurements later in development. This study supports the use of longitudinal approaches to investigate the neural basis of the developmental process of learning to read and the application of triangulation, i.e. using multiple research approaches to help gain more insight and aiding the interpretation of obtained results.

Rapid and widespread changes in brain anatomy and physiology in the first five years of life present substantial challenges for developmental structural, functional, and diffusion MRI studies. One persistent challenge is that methods best suited to earlier developmental stages are suboptimal for later stages, which engenders a trade-off between using different, but age-appropriate, methods for different developmental stages or identical methods across stages. Both options have potential benefits, but also biases, as pipelines for each developmental stage can be matched on methods or the age-appropriateness of methods, but not both. This review describes the data acquisition, processing, and analysis challenges that introduce these potential biases and attempts to elucidate decisions and make recommendations that would optimize developmental comparisons.

Phonological processing skills are known as the most robust cognitive predictor of reading ability. Therefore, the neural determinants of phonological processing have been extensively investigated by means of either neurofunctional or neurostructural techniques. However, to fully understand how the brain represents and processes phonological information, there is need for studies that combine both methods. The present study applies such a multimodal approach with the aim of investigating the pre-reading relation between neural measures of auditory temporal processing, white matter properties of the reading network and phonological processing skills. We administered auditory steady-state responses, diffusion-weighted MRI scans and phonological awareness tasks in 59 pre-readers. Our results demonstrate that a stronger rightward lateralization of syllable-rate (4 Hz) processing coheres with higher fractional anisotropy in the left fronto-temporoparietal arcuate fasciculus. Both neural features each in turn relate to better phonological processing skills. As such, the current study provides novel evidence for the existence of a pre-reading relation between functional measures of syllable-rate processing, structural organization of the arcuate fasciculus and cognitive precursors of reading development. Moreover, our findings demonstrate the value of combining different neural techniques to gain insight in the underlying neural systems for reading (dis)ability.

Pediatric brain volumetric analysis based on Magnetic Resonance Imaging (MRI) is of particular interest in order to understand the typical brain development and to characterize neurodevelopmental disorders at an early age. However, it has been shown that the results can be biased due to head motion, inherent to pediatric data, and due to the use of methods based on adult brain data that are not able to accurately model the anatomical disparity of pediatric brains. To overcome these issues, we proposed childmetrix, a tool developed for the analysis of pediatric neuroimaging data that uses an age-specific atlas and a probabilistic model-based approach in order to segment the gray matter (GM) and white matter (WM). The tool was extensively validated on 55 scans of children between 5 and 6 years old (including 13 children with developmental dyslexia) and 10 pairs of test-retest scans of children between 6 and 8 years old and compared with two state-of-the-art methods using an adult atlas, namely icobrain (applying a probabilistic model-based segmentation) and Freesurfer (applying a surface model-based segmentation). The results obtained with childmetrix showed a better reproducibility of GM and WM segmentations and a better robustness to head motion in the estimation of GM volume compared to Freesurfer. Evaluated on two subjects, childmetrix showed good accuracy with 82–84% overlap with manual segmentation for both GM and WM, thereby outperforming the adult-based methods (icobrain and Freesurfer), especially for the subject with poor quality data. We also demonstrated that the adult-based methods needed double the number of subjects to detect significant morphological differences between dyslexics and typical readers. Once further developed and validated, we believe that childmetrix would provide appropriate and reliable measures for the examination of children's brain. Keywords: Brain volumetric analysis, Neuroimaging data, Pediatric atlas, Child-adjusted processing, Magnetic resonance imaging

Neural anomalies have been demonstrated in dyslexia. Recent studies in pre-readers at risk for dyslexia and in pre-readers developing poor reading suggest that these anomalies might be a cause of their reading impairment. Our study goes one step further by exploring the neurodevelopmental trajectory of white matter anomalies in pre-readers with and without a familial risk for dyslexia (n = 61) of whom a strictly selected sample develops dyslexia later on (n = 15). We collected longitudinal diffusion MRI and behavioural data until grade 3. The results provide evidence that children with dyslexia exhibit pre-reading white matter anomalies in left and right long segment of the arcuate fasciculus (AF), with predictive power of the left segment above traditional cognitive measures and familial risk. Whereas white matter differences in the left AF seem most strongly related to the development of dyslexia, differences in the left IFOF and in the right AF seem driven by both familial risk and later reading ability. Moreover, differences in the left AF appeared to be dynamic. This study supports and expands recent insights into the neural basis of dyslexia, pointing towards pre-reading anomalies related to dyslexia, as well as underpinning the dynamic character of white matter. Keywords: Developmental dyslexia, Reading, White matter, DTI, Arcuate fasciculus, IFOF

A child's school achievement is influenced by environmental factors. The environmental factors, when represented by socio-economic status (SES) of the family, have been demonstrated to be related to the reading skills of a child. The neural correlates of the relation between SES and reading have been less thoroughly investigated. The present study expands current research by exploring the relation between SES, quantified by paternal educational level, reading of the offspring and the structure of white matter pathways in the left hemisphere as derived from DTI-based tractography analyses. Therefore, three dorsal white matter pathways, i.e. the long, anterior and posterior segments of the arcuate fasciculus (AF), and three ventral white matter pathways, i.e. the inferior fronto-occipital fasciculus (IFOF), the inferior longitudinal fasciculus (ILF) and the uncinate fasciculus (UF), were manually dissected in the left hemisphere of 34 adolescents with a wide range of reading skills. The results demonstrated a relation between word reading, SES quantified by paternal educational level, and fractional anisotropy (FA) within the left dorsal AF segment and the left ventral UF. Thus, the present study proposes a relationship between paternal educational level and a specific white matter pathway that is important for reading, aiming to guide future research that can determine processes underlying this relationship.

In this study, we examined the learning of new grapheme-phoneme correspondences in individuals with and without dyslexia. Additionally, we investigated the relation between grapheme-phoneme learning and measures of phonological awareness, orthographic knowledge and rapid automatized naming, with a focus on the unique joint variance of grapheme-phoneme learning to word and non-word reading achievement. Training of grapheme-phoneme associations consisted of a 20-min training program in which eight novel letters (Hebrew) needed to be paired with speech sounds taken from the participant's native language (Dutch). Eighty-four third grade students, of whom 20 were diagnosed with dyslexia, participated in the training and testing. Our results indicate a reduced ability of dyslexic readers in applying newly learned grapheme-phoneme correspondences while reading words which consist of these novel letters. However, we did not observe a significant independent contribution of grapheme-phoneme learning to reading outcomes. Alternatively, results from the regression analysis indicate that failure to read may be due to differences in phonological and/or orthographic knowledge but not to differences in the grapheme-phoneme-conversion process itself.

In adults and school-aged children, phonological aspects of reading seem to be sustained by left dorsal regions, while ventral regions seem to be involved in orthographic word recognition. Yet, given that the brain reorganises during reading acquisition, it is unknown when and how these reading routes emerge and whether neural deficits in dyslexia predate reading onset. Using diffusion MRI in 36 pre-readers with a family risk for dyslexia (FRD+) and 35 well matched pre-readers without a family risk (FRD−), our results show that phonological predictors of reading are sustained bilaterally by both ventral and dorsal tracts. This suggests that a dorsal and left-hemispheric specialisation for phonological aspects of reading, as observed in adults, is presumably gradually formed throughout reading development. Second, our results indicate that FRD+ pre-readers display mainly white matter differences in left ventral tracts. This suggests that atypical white matter organisation previously found in dyslexic adults may be causal rather than resulting from a lifetime of reading difficulties, and that the location of such a deficit may vary throughout development. While this study forms an important starting point, longitudinal follow-up of these children will allow further investigation of the dynamics between emerging literacy development and white matter connections.

Neural anomalies have been demonstrated in dyslexia. Recent studies in pre-readers at risk for dyslexia and in pre-readers developing poor reading suggest that these anomalies might be a cause of their reading impairment. Our study goes one step further by exploring the neurodevelopmental trajectory of white matter anomalies in pre-readers with and without a familial risk for dyslexia (n = 61) of whom a strictly selected sample develops dyslexia later on (n = 15). We collected longitudinal diffusion MRI and behavioural data until grade 3. The results provide evidence that children with dyslexia exhibit pre-reading white matter anomalies in left and right long segment of the arcuate fasciculus (AF), with predictive power of the left segment above traditional cognitive measures and familial risk. Whereas white matter differences in the left AF seem most strongly related to the development of dyslexia, differences in the left IFOF and in the right AF seem driven by both familial risk and later reading ability. Moreover, differences in the left AF appeared to be dynamic. This study supports and expands recent insights into the neural basis of dyslexia, pointing towards pre-reading anomalies related to dyslexia, as well as underpinning the dynamic character of white matter. [ABSTRACT FROM AUTHOR]

Due to differences in hydraulic conductivity and effects of well construction geometry, groundwater lateral flow through a monitoring well typically differs from groundwater flow in the surrounding aquifer. These differences must be well understood in order to apply passive measuring techniques, such as passive flux meters (PFMs) used for the measurement of groundwater and contaminant mass fluxes. To understand these differences, lab flow tank experiments were performed to evaluate the influences of the well screen, the surrounding filter pack and the presence of a PFM on the natural groundwater flux through a monitoring well. The results were compared with analytical calculations of flow field distortion based on the potential theory of Drost et al. (1968). Measured well flow field distortion factors were found to be lower than calculated flow field distortion factors, while measured PFM flow field distortion factors were comparable to the calculated ones. However, this latter is not the case for all conditions. The slotted geometry of the well screen seems to make a correct analytical calculation challenging for conditions where flow field deviation occurs, because the potential theory assumes a uniform flow field. Finally, plots of the functional relationships of the distortion of the flow field with the hydraulic conductivities of the filter screen, surrounding filter pack and corresponding radii make it possible to design well construction to optimally function during PFM applications. [ABSTRACT FROM AUTHOR]

In adults and school-aged children, phonological aspects of reading seem to be sustained by left dorsal regions, while ventral regions seem to be involved in orthographic word recognition. Yet, given that the brain reorganises during reading acquisition, it is unknown when and how these reading routes emerge and whether neural deficits in dyslexia predate reading onset. Using diffusion MRI in 36 pre-readers with a family risk for dyslexia (FRD + ) and 35 well matched pre-readers without a family risk (FRD − ), our results show that phonological predictors of reading are sustained bilaterally by both ventral and dorsal tracts. This suggests that a dorsal and left-hemispheric specialisation for phonological aspects of reading, as observed in adults, is presumably gradually formed throughout reading development. Second, our results indicate that FRD + pre-readers display mainly white matter differences in left ventral tracts. This suggests that atypical white matter organisation previously found in dyslexic adults may be causal rather than resulting from a lifetime of reading difficulties, and that the location of such a deficit may vary throughout development. While this study forms an important starting point, longitudinal follow-up of these children will allow further investigation of the dynamics between emerging literacy development and white matter connections. [ABSTRACT FROM AUTHOR]

Abstract: Due to the use of standard electrodes electrochemical milling avoids the complex electrode design which is often a burden in sinking ECM. In this process material is removed by a tubular tool following a predefined path in a layer-by-layer fashion. In this initial study the influence of different process parameters, electrode geometry and electrode rotation on the process performance is investigated. Experiments showed that the best performance in terms of removal rate, surface quality and accuracy can be obtained when using a pulsed voltage input. Moreover, inaccuracies due to the tubular electrode shape can be avoided by using alternative electrodes which distribute the flushing holes over the entire cross section of the electrode or by decreasing the inner diameter of the tubular electrodes. Finally specific milling aspects like performing multiple passes and step-over were investigated. It was shown that further improvements are necessary to obtain a good part accuracy. [Copyright &y& Elsevier]

Abstract: This paper describes the development and validation of an operations evaluation system for sinking EDM operations. Based on a given workpiece geometry (e.g. mould), regions to be EDM’ed are automatically indentified. For a given electrode configuration, consisting of one or more regions, EDM machining times are calculated, making a proper process planning possible. The EDM time calculation is based on reference values for machining times which are then corrected for changes in the electrode geometry and generator settings. The developed system has been validated, proving a better and more accurate machining time estimation. [Copyright &y& Elsevier]

Objectives: The Group for the Respect and Excellence in Science (GREES) has reviewed and updated their recommendations for clinical trials to evaluate the efficacy and safety of new chemical entities to be used in the treatment and prevention of glucocorticoid-induced osteoporosis (GIOP). Methods: Consensus discussion of the committee. Results: With the exception of steroid use posttransplantation, there is no need to differentiate between underlying diseases. Prevention and treatment for GIOP are dependent on exposure to glucocorticoids rather than T-scores as in postmenopausal osteoporosis (PMO). If fracture data are obtained for PMO, it need not be repeated for GIOP, relying instead on bone mineral density (BMD) trials of at least 1 year. GREES recommends several changes in the previous guidance for GIOP. The committee saw no need to repeat preclinical studies if those have been previously done to assure bone quality in PMO. Similarly, phase I and phase II trials, if careful dose selection has been done for PMO, should not be repeated. The “prevention” and “treatment” claims should remain. Since the most recent evidence suggests significant increase in fracture risk for daily doses of prednisone of 5 mg/day or equivalent, clinical trials should concentrate on patients receiving at least this daily dosage. The emergence of bisphosphonates as the reference treatment, together with the rapid bone loss and high fracture incidence in glucocorticoid users, necessitates recommending a noninferiority trial design with lumbar spine BMD as the primary endpoint after 1 year. Conclusions: Registration of new chemical entities to be used in the management of GIOP should be granted, based on a 1-year noninferiority trial, using BMD as primary outcome and alendronate or risedronate as comparator. Demonstration of antifracture efficacy should have been previously demonstrated in PMO. [Copyright &y& Elsevier]

The activities of the newer antipseudomonal agents cefsulodin, ceftazidime, U-63196, aztreonam and piperacillin were compared, together with azlocillin, carbenicillin, ticarcillin and tobramycin against 98 strains of . On all of the 43 isolates from cystic fibrosis patients and the 55 strains from other chronically infected patients, ceftazidime (MIC: 5·0 and 2·8 mg/I respectively) and cefsulodin (MIC: 8·2 and 3·1 mg/l) were the most active cephalosporins, and U-63196 the least active (MIC: 40·1 and 46·1 mg/I). A high incidence of resistance (23 of 55 strains) to tobramycin was found only in the non-cystic fibrosis isolates. The activity of the other agents was comparable in the cystic fibrosis and non-cystic fibrosis isolates. MIC for aztreonam were 15·8 and 13·6 mg/l. Piperacillin was the most active penicillin in both populations (MIC: 25·8 and 21·8 mg/l). Cross resistance was demonstrated in both populations for the penicillin compounds. [ABSTRACT FROM PUBLISHER]

Rapid and widespread changes in brain anatomy and physiology in the first five years of life present substantial challenges for developmental structural, functional, and diffusion MRI studies. One persistent challenge is that methods best suited to earlier developmental stages are suboptimal for later stages, which engenders a trade-off between using different, but age-appropriate, methods for different developmental stages or identical methods across stages. Both options have potential benefits, but also biases, as pipelines for each developmental stage can be matched on methods or the age-appropriateness of methods, but not both. This review describes the data acquisition, processing, and analysis challenges that introduce these potential biases and attempts to elucidate decisions and make recommendations that would optimize developmental comparisons. [ABSTRACT FROM AUTHOR]

Phonological processing skills are known as the most robust cognitive predictor of reading ability. Therefore, the neural determinants of phonological processing have been extensively investigated by means of either neurofunctional or neurostructural techniques. However, to fully understand how the brain represents and processes phonological information, there is need for studies that combine both methods. The present study applies such a multimodal approach with the aim of investigating the pre-reading relation between neural measures of auditory temporal processing, white matter properties of the reading network and phonological processing skills. We administered auditory steady-state responses, diffusion-weighted MRI scans and phonological awareness tasks in 59 pre-readers. Our results demonstrate that a stronger rightward lateralization of syllable-rate (4 Hz) processing coheres with higher fractional anisotropy in the left fronto-temporoparietal arcuate fasciculus. Both neural features each in turn relate to better phonological processing skills. As such, the current study provides novel evidence for the existence of a pre-reading relation between functional measures of syllable-rate processing, structural organization of the arcuate fasciculus and cognitive precursors of reading development. Moreover, our findings demonstrate the value of combining different neural techniques to gain insight in the underlying neural systems for reading (dis)ability. [ABSTRACT FROM AUTHOR]