Brain imaging and outcome in extremely preterm infants

In parallel to the dawn of modern neonatal intensive care, the survival after extremely preterm birth has greatly improved. These very immature children are born during a vulnerable phase of brain maturation, and are at high risk of brain injury and subsequent neurodevelopmental impairments. The overall aim of the works compiled in this thesis is to study brain development and damage of extremely preterm (EPT) infants using different neuroimaging techniques, and to investigate the relations to toddler age outcomes. All infants born before gestational week 27 + 0 days in Stockholm during a 3-year period were invited to participate. Infants underwent Magnetic Resonance Imaging (MRI, n=109) including Diffusion Tensor Imaging (DTI, n=54) at term equivalent age. Paper I describes the brain damage panorama in the cohort, and the rates of major injuries were low; only 14% had moderate or severe white matter (WM) abnormalities. Subtle WM changes, so called DEHSI (diffuse excessive high signal intensities), were found in 56% of infants and were verified as changes on DTI, indicating possible alterations in WM microstructure. To study functional connectivity in the WM we used non-stimulated functional MRI in EPT infants at rest. In Paper II, we present evidence of five unique resting state networks at term age in healthy preterm infants. In Paper III we demonstrate that, provided that imaging was performed on the same day, cranial ultrasound (cUS) detected all infants with moderate or severe WM abnormalities on MRI. However, one third of infants with mild WM abnormalities and four infants with small cerebellar haemorrhages on MRI were overlooked with cUS. Follow-up assessments were performed at age 30 months corrected to study the consequences of extreme prematurity. In Paper IV, infants underwent a neurological examination and were evaluated using the Bayley Scales of Infant and Toddler Development (BSID-III) to assess cognitive, language and motor function. Overall, the preterm group performed within the normal range for test standards, but significantly lower than a full term control group. The rates of severe impairments were low; 2% had a severe cognitive delay, 5% had a severe language delay and 7% had cerebral palsy. Moreover in Paper IV, we demonstrate a high negative predictive value of a normal MRI at term age. Cystic changes, delayed myelination and severe WM reduction were factors most strongly related to adverse outcomes. DEHSI showed no relation to later cognitive, language and motor performances. Finally in Paper V, we found poorer cognitive and language function in EPT boys than girls at age 30 months. These differences could neither be explained by an altered WM microstructure assessed with MR-DTI and Tract-Based Spatial Statistics, nor by any individual perinatal factor. In summary, the rates of brain injuries and later impairments were low in this very high-risk population. The present results suggest that survival without major disability is likely even at extremely low gestational ages. Long-term follow-up after extremely preterm birth is essential

Timing of Svecofennian crustal growth and collisional tectonics in Åland, SW Finland

In an effort to quantify the time parameter in the tectonomagmatic evolution of what has been called the Southern Svecofennian Arc Complex (SSAC) of SW Finland, advanced radiometric dating techniques have here been applied to rock groups of key importance in that area. In this paper we report the results of 131 high-resolution ionmicroprobe spot analyses (SIMS) of zircons, and 33 measurements using isotope dilution mass spectrometry (ID-TIMS) on zircon, monazite and titanite, and employing both large-sample multi-grain as well as single-grain techniques. The Torsholma area of the Åland archipelago, situated between southern Finland and central Sweden, is a key structural area significant to resolve the time dimension in Svecofennian tectonics. There a collage of imbricated rock slabs was formed by tectonic shortening representing the culmination of large-scale penetrative Svecofennian deformation. Another structurally significant feature investigated is the South FinlandShear Zone (SFSZ) that transects the southwest-Finnish archipelago and further east follows the southern coast of Finland. This shear zone forms the southern limit of the c. 1830 Ma Late Svecofennian Granite and Migmatite Zone (LSGM) and also features deformations of a later stage when the considered region of Svecofennian crust was consolidated. The obtained age results and their tectonic analysis can be summarized as follows. The Enklinge volcanic sequence (1885±6 Ma) is within error limits coeval with the intrusion of abundant early-kinematic gneissose granodiorites whose average age of 1884±5 Ma marks the formation of new crust in this region. Some of these geisses contain a significant amount of 2000–2080 Ma zircon. Although many Svecofennian granitoids are known to contain heterogeneous zircon populations, mainly formed c. 1890 Ma ago but also containing an inherited component, the Kökar gneiss is, to the best of our knowledge, the first case where inheritance from c. 2030 Ma sources has been unequivocally demonstrated in a syntectonic Svecofennian intrusive rock. At Torsholma, granodiorites (1879±6 Ma) have similarly intruded the supracrustal series, but there they were later metamorphosed into granulite orthogneisses. The mesoscopic recumbent folds and subhorizontal schistosity of these gneisses were transected by a set of steep amphibolitic dykes indicating an episode of extension. During a preceding stage, these gneisses had been sandwiched like an allochthonous slab unit between the supracrustal rocks. Younger sheet-like granodioritic intrusions (1861±19 Ma) with associated dykes (1865±7 Ma) reflect an even later stage of collisional thrusting. Altogether this tectonic evolution lasted for approximately 15 Ma (c. 1875–1860 Ma) and records a period of significant deformations during the Svecofennian orogeny. Monazites and zircon rims yield concordant U-Pb ages of c. 1830 Ma. Thisis in agreement with previously obtained ages of late Svecofennian granites and migmatites in the LSGM zone in S Finland. Weakly deformed pegmatites and even-grained granite dykes were emplaced1790±6 Ma ago and intersect the other rocks of the area. They characterize the vaning stages of shearing along the northwestern part of the SFSZ, and the establishment of a consolidated crust where deformation was about to cease by this time

Report No. 19: Geographic Mobility in the European Union: Optimising its Economic and Social Benefits

Joint expertise with NIRAS Consultants and AMS for the European Commission, Bonn 2008 (159 pages)

Clinical implications of diffuse excessive high signal intensity (DEHSI) on neonatal MRI in school age children born extremely preterm

Objective: Magnetic resonance imaging (MRI) of the brain carried out during the neonatal period shows that 55–80% of extremely preterm infants display white matter diffuse excessive high signal intensity (DEHSI). Our aim was to study differences in developmental outcome at the age of 6.5 years in children born extremely preterm with and without DEHSI.Study Design: This was a prospective cohort study of 83 children who were born in Stockholm, Sweden, between 2004 and 2007, born at gestational age of < 27 weeks + 0 days and who underwent an MRI scan of their brain at term equivalent age. The outcome measures at 6.5 years included testing 66 children with the modified Touwen neurology examination, the Movement Assessment Battery for Children 2, the Wechsler Intelligence Scale for Children—Fourth Edition, Beery Visual-motor Integration test—Sixth Edition, and the Strengths and Difficulties Questionnaire. Group-wise comparisons were done between children with and without DEHSI using Student t-test, Mann Whitney U test, Chi square test and regression analysis.Results: DEHSI was detected in 39 (59%) of the 66 children who were assessed at 6.5 years. The presence of DEHSI was not associated with mild neurological dysfunction, scores on M-ABC assessment, cognition, visual-motor integration, or behavior at 6.5 years.Conclusion: The presence of qualitatively defined DEHSI on neonatal MRI did not prove to be a useful predictor of long-term impairment in children born extremely preterm

PP063—Changes in the utilisation of venlafaxine after the introduction of generics in Sweden: Implications for other countries

2013 e37 Significant but lesser changes in losartan utilization were seen in Austria and Belgium. There was no change in losartan utilization patterns in Scotland or Spain. Losartan typically generic at low prices, leading to appreciable increases in prescribing efficiency in NHS Bury, Sweden, Austria, and Belgium. There were some savings in Scotland with generic losartan. Conclusion: Multiple demand-side measures appreciably enhanced ARB prescribing efficiency. This mirrors previous findings that multiple measures are need to change prescribing habits. No significant increase in losartan utilization following generics where countries have not instigated specific measures suggests authorities cannot rely on a "spillover" effect between classes to change physician prescribing habits. This is the case even with multiple demand-side activities encouraging preferential prescribing of generics in related classes. This may be exacerbated on this occasion by a more complex message; for example, away from ACEIs first line versus ARBs to ACEIs + low cost ARBs first line. Disclosure of Interest: None declared

Policies for biosimilar uptake in Europe : an overview

Background: Across European countries, differences exist in biosimilar policies, leading to variations in uptake of biosimilars and divergences in savings all over Europe. Objectives: The aim of this article is to provide an overview of different initiatives and policies that may influence the uptake of biosimilars in different European countries. Recommendations will be formulated on how to create sustainable uptake. Methods: An overview of policies on biosimilars was obtained via a questionnaire, supplemented with relevant articles. Topics were organized in five themes: availability, pricing, reimbursement, demand-side policies, and recommendations to enhance uptake. Results: In all countries studied, biological medicines are available. Restrictions are mainly dependent on local organization of the healthcare system. Countries are willing to include biosimilars for reimbursement, but for commercial reasons they are not always marketed. In two thirds of countries, originator and biosimilar products may be subjected to internal reference pricing systems. Few countries have implemented specific incentives targeting physicians. Several countries are implementing pharmacist substitution; however, the scope and rules governing such substitution tend to vary between these countries. Reported educational policies tend to target primarily physicians, whereas fewer initiatives were reported for patients. Recommendations as proposed by the different country experts ranged from the need for information and communication on biosimilars to competitive pricing, more support for switching and guidance on substitution. Conclusions: Most countries have put in place specific supply-side policies for promoting access to biosimilars. To supplement these measures, we propose that investments should be made to clearly communicate on biosimilars and educate stakeholders. Especially physicians need to be informed on the entry and use of biosimilars in order to create trust. When physicians are well-informed on the treatment options, further incentives should be offered to prescribe biosimilars. Gainsharing can be used as an incentive to prescribe, dispense or use biosimilars. This approach, in combination with binding quota, may support a sustainable biosimilar market

Neuroepigenetics of preterm white matter injury

Introduction: Preterm birth is increasing worldwide and is a major cause of neonatal death. Survivors are at increased risk of neurodisability, cognitive, social and psychiatric disorders in later life. Alterations to the white matter can be assessed using diffusion tensor imaging (DTI) MRI and are associated with poor neurodevelopmental outcome. The pathogenesis of white matter injury is multifactorial and several clinical risk and resilience factors have been identified. DNA methylation (DNAm) is an epigenetic process which links stressful early life experience to later life disease and is associated with normal brain development, neuronal processes and neurological disease. Several studies have shown DNAm is altered by the perinatal environment, however its role in preterm white mater injury is yet to be investigated. Aims: 1. To examine the relationship between preterm birth and white matter integrity 2. To investigate the effect of neuroprotective treatments and deleterious clinical states on white matter integrity in preterm infants 3. To assess the best DTI method of quantifying white matter integrity in a neonatal population 4. To investigate the effect of preterm birth on DNA methylation and 5. To determine the clinical and imaging factors that contribute to the variance in DNA Methylation caused by preterm birth Methods: DTI data was acquired from preterm infants (< 32 weeks’ gestation or < 1500 grams at birth) at term equivalent age (TEA) and term controls (> 37 weeks’ gestation at birth). Region-of-interests (ROI) and tract-averaged methods of DTI analysis were performed to obtain measurements of fractional anisotropy (FA) and mean diffusivity (MD) in the genu of corpus callosum, posterior limb of internal capsule and centrum semiovale. Clinical data was collected for all infants and the effect of prematurity, neuroprotective agents and clinical risk factors on white matter integrity were analysed. 8 major white matter tracts were segmented using probabilistic neighbourhood tractography (PNT), a tract-averaged technique which also allowed the calculation of tract shape. The two DTI techniques were compared to evaluate agreement between results. DNA was collected from preterm infants and term controls at TEA, and a genome-wide analysis of DNAm was performed. DTI parameters from probabilistic neighborhood tractography (PNT) methodology and clinical risk and resilience factors were used to inform a principal components analysis to investigate the contribution of white matter integrity and clinical variables to variance in DNAm. Results: FA and MD were significantly affected by preterm birth on ROI analysis. In addition, DTI parameters were affected by clinical factors that included antenatal magnesium sulphate, histological chorioamnionitis and bronchopulmonary dysplasia. Evaluation of DTI methodology revealed good accuracy in repeated ROI measurements but limited agreement with tract-averaged values. Differential methylation was found within 25 gene bodies and 58 promoters of protein-coding genes in preterm infants, compared with controls. 10 of these genes have a documented association with neural function or neurological disease. Differences detected in the array were validated with pyrosequencing which captured additional differentially methylated CpGs. Ninety-five percent of the variance in DNAm in preterm infants was explained by 23 principal components (PC); corticospinal tract shape associated with 6th PC, and gender and early nutritional exposure associated with the 7th PC. Conclusions: Preterm birth is associated with alterations in white matter integrity which is modifiable by clinical risk factors and neuroprotective agents. ROI analysis may not provide sufficient representation of white matter tracts in their entirety. Prematurity is related to alterations in the methylome at sites that influence neural development and function. Differential methylation analysis has identified several promising candidate genes for future work and contributed to the understanding of the pathogenesis of preterm brain injury

Communication in the Mathematics Classroom – An Observa-tional study about teachers´ questions during mathematical lessons in the lower primary school

Syftet med studien är att identifiera och beskriva vilka sorts frågor lärare ställer till eleverna under matematematiklektioner, hur eleverna besvarar dem och hur frågorna möjliggör elever-nas lärande i matematik. Studien kombinerar det sociokulturella och det socialkonstruktivist-iska perspektivet på lärande för att med dessa som utgångspunkt rama in begrepp som kommu-nikation och reflektion samt dess betydelse i matematikundervisningen. För att analysera frå-gorna har ett analysverktyg (Cunningham, 1987) använts för att kategorisera frågor utifrån vil-ken kognitiv nivå de möjliggör. För att möta syftet och eftersom det är kommunikation mellan lärare och elever som analyseras har videoinspelade observationer använts som datainsamlings-metod. Material från två lärares matematiklektioner har transkriberats, kodats och analyserats utifrån analysverktyget. De två lektionernas innehåll baseras på arbetssättet Context for Le-arning Mathematics (Fosnot & Dolk, 2001) men med olika innehåll i de två klasserna som motsvarar årskurs 1 och 3 i Sverige. Huvudresultatet av studien visar att faktafrågor och konceptuella låg-konvergenta frågor är de som dominerar i båda lärarnas matematikundervisning. Elevernas besvarande av dessa frågor var korta i form av ja, nej eller något av de alternativ som lärarna frågade efter. Däremot visade resultatet att de lägre kognitiva frågorna ligger till grund för att läraren ska kunna ställa de högre kognitiva frågorna. Med de förstnämnda frågorna fick lärarna reda på elevernas svar av sum-man/produkten av två tal, elevernas tänkande eller tillvägagångssätt, vilket verkade avgörande för att efterhand kunna komplettera med de högre kognitiva frågorna där elevernas svar blev längre och innehöll bland annat förklaringar, analys och reflektion

Förflyttning av tidigare existerande filmmusik : Tekniska aspekter och narratologiska implikationer av hörbara diegetiska övergångar i Joker och andra filmer

This thesis concerns itself with a phenomenon found in film music that can be described as audible diegetic transitions. In short, an audible diegetic transition occurs when film music shifts from one implied musical placement to another by changing its pre­sented sound quality. This occurs predominantly through the employment of music that is pre-existing in relation to the release of the film where the music is utilised. These audible diegetic transitions are categorised as aural displacements and transaural dis­placements which are both anchored in previous re­search concerning stable musical place­ments. In order to answer the research questions regarding technical aspects and narra­tological implications, the thesis is centred around a film music analysis. The de­marcation of said analysis uses pre-existing songs from the film Joker (Philips, 2019) as its main focus. In order to provide a colourful and meaningful discussion the selected material also contains a variety of examples from other films. The analysis shows that the selected audible diegetic transitions can provide narra­tological implications both for a film as a whole and for a specific scene or se­quence in any film. In Joker specifically, the audible diegetic transitions arguably contain the narra­to­logi­cal im­plication of adding to the retrospective and unreliable narration, which is im­port­ant for the story of the film. The thesis also argues that the technical aspects of the ana­lysed audible diegetic transitions can be condensed into being either diegetic to comm­en­tary, or vice versa. Diegetic music is, in this context, defined as music that is im­­­­plied as being heard in the acoustic space of the story-world, whereas commen­tary music is an um­brella term defined as music that is not implied being heard in the acous­tic space of the story-world. The analysis shows that these transitions can transpire either instantly or gra­­­dually with the change of sound quality from being either narrow or wide. These tech­nical aspects contribute in under­standing the narratological im­plications of said au­dible diegetic transition by categorising them as either emotive or groun­ding. Both of these narratological implications can be concluded and described as swift enforcers of the relationship be­tween the one consuming the film and the char­acters, or lo­cations, of the film they are con­­­­suming. Audible diegetic transitions figura­tively breach the fourth wall that is the screen