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Purpose: To analyze serum estradiol (E2) and estrone (E1) during letrozole treatment and their association to Quality of Life (QoL) and side-effects., Methods: Postmenopausal breast cancer patients starting adjuvant letrozole were eligible. Serum samples were taken at baseline, three, and 12 months. E2 and FSH were measured with routine chemiluminescent immunoassays. E2 and E1 were analyzed after trial completion with a highly sensitive liquid chromatography-tandem mass spectrometry method (LC-MS/MS) with lower limits of quantification (LLOQ) of 5 pmol/L. QoL was measured at baseline and at 12 months with the EORTC QLQ-C30 and QLQ-BR23 and the Women's Health questionnaires, and menopause-related symptoms with the modified Kupperman Index., Results: Of 100 screened patients 90 completed the trial. Baseline mean LC-MS/MS E2 and E1 were 12 pmol/L (range < 5-57) and 66 pmol/L (< 5-226), respectively. E2 levels measured by immunoassay and LC-MS/MS showed no correlation. E2 and E1 were completely suppressed by letrozole except for one occasion (E1 11 pmol/L at 3 months). Pain, side effects of systemic therapy, vasomotor symptoms, joint and muscle aches, and vaginal dryness increased during letrozole treatment. A high baseline E2 was significantly associated with increased aching joints and muscles, but not with the other side effects., Conclusions: Letrozole supresses E2 and E1 completely below the LLOQ of the LC-MS/MS in postmenopausal women. High pre-treatment E2 levels were associated with more joint and muscle pain during letrozole. Automated immunoassays are unsuitable for E2 monitoring during letrozole therapy due to poor sensitivity., (© 2023. The Author(s).)

Unlike many believe, accurate and fluent basic reading skill (ie. to decode text) is not enough for learning knowledge via reading. More than 10 years ago a digital learning game supporting the first step towards full literacy, i.e., GraphoGame (GG) was developed by the first author with his colleagues in the University of Jyväskylä, Finland. It trains the acquisition of basic reading skills, i.e., learning to sound out written language. Nowadays, when almost everyone in the world has an opportunity to use this GG, it is time to start supporting the acquisition of full literacy (FL). FL is necessary for efficient learning in school, where reading the schoolbooks successfully is essential. The present plan aims to help globally almost all who read whatever orthography to start from the earliest possible grade during which children have learned the mastery of the basic reading skill to immediately continue taking the next step to reach FL. Unlike common beliefs, support of FL is mostly needed among those who read transparent orthographies (reading by the majority of readers of alphabetic writings) which are easier to sound out due to consistency between spoken and written units at grapheme-phoneme level. This makes readers able to sound any written item which is pronounceable with only a little help of knowing what it means. Therefore, children tend to become inclined to not pay enough attention to the meaning but concentrate on decoding the text letter-by-letter. They had to learn from the beginning to approach the goal of reading, mediation of the meaning of the text. Readers of nontransparent English need to attend morphology for correct sounding. The continuing fall of OECD's Program for International Student Assessment (PISA) results, e.g., in Finland reveals that especially boys are not any more interested in reading outside school which would be natural way to reach the main goal of reading, FL. What could be a better way to help boys towards FL than motivating them to play computer games which requires reading comprehension. The new digital ComprehensionGame designed by the first author motivates pupils to read in effective way by concurrently elevating their school achievements by connecting the training to daily reading lessons. This article describes our efforts to elaborate and validate this new digital tool by starting from populations of learners who need it most in Africa and in Finland., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lyytinen and Louleli.)

Possibly some of the most important skills that one can have are those needed to become fully literate. We all wish our children to reach such a goal. Unfortunately, the focus of attention in reading research has been on acquiring readiness to sound out written language, i.e., the basic reading skills. Full literacy is the readiness to learn knowledge by reading. Thus, one has to be able to take two steps to reach full literacy. Indications related to both of these steps can be observe in the brain. This may be easiest when we observe the brain activity of a learner who faces difficulties in taking these steps. In fact, the serious difficulty of taking the first step can be observed soon after birth, shown below as a summary of relevant details from the paper published earlier in this journal. The step from a basic reading skill to reading comprehension requires that one must learn to read for the mediating meanings of the text, i.e., its morphological information, on top of the phonological one. This can also be approached using brain-related observations, as we show here, too. Taking these steps varies between orthographies. Here, we illustrate the learning of these steps in the context of transparently written alphabetic writings by choosing it as our concrete example because its readers form the majority of readers of alphabetic writings. After learning these facts, we had to be able to help those who face difficulties in these steps to overcome her/his bottlenecks. We summarize how we have tried to do that. Each step can be taken using a digital game-like training environment, which, happily, is now open to be distributed for the use of (almost) all in the world. How we have already tried that concerning the first step is illustrated below. Additionally, how we plan to do that concerning the second step, the final goal, completes our present story.

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10 -8 ) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p  < 2.8 × 10 -6 ) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at p T  = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p  = 8 × 10 -13 ), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10 -43 ), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10 -22 ), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10 -12 ), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10 -4 ), educational attainment (0.86[0.82; 0.91]; p = 2 × 10 -7 ), and intelligence (0.72[0.68; 0.76]; p = 9 × 10 -29 ). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence., (© 2020. The Author(s).)

Purpose: To analyze whether monitoring serum estradiol (E2) levels using a highly sensitive and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) method may identify patients with AI failure with E2 levels below the lower limit of quantification (LLOQ) after schwitching from tamoxifen to letrozole., Methods: In a prospective study of breast cancer patients switching to letrozole treatment after previous tamoxifen, plasma estrogen levels were measured at baseline and after 3- and 12-months using LC-MS/MS., Results: Forty-six patients were classified postmenopausal and entered into the final analysis. Thirty-nine (85%) patients had three- and 12-month E2 concentrations below the LLOQ (5 pmol/L). In the seven patients classified as AI-failures during letrozole treatment, serum E2-MS level rose above 5 pmol/L at 3 months with a mean E2-MS 77.5 pmol/L or 12 months with a mean E2-MS 21 pmol/L. None of the baseline variables i.e., age at diagnosis, age at study entry, age at menarche, BMI, endometrial thickness, total ovarian volume, baseline FSH, E2-IA, or E2-MS were significantly associated with the risk of AI failure in logistic regression. E2 levels at baseline measured by E2-IA did not significantly correlate to the levels measured by E2-MS., Conclusions: There is a relatively high risk of inadequate estrogen suppression in patients who switch from tamoxifen treatment to AIs. The use of sensitive and specific assays, such as LC-MS/MS methods, to monitor estrogen levels during AI treatment is essential to minimize the risk of a proceeding inefficient endocrine therapy.

This paper discusses how the association learning principle works for supporting acquisition of basic spelling and reading skills using digital game-based learning environment with the Finland-based GraphoLearn (GL) technology. This program has been designed and validated to work with early readers of different alphabetic writing systems using repetition and reinforcing connections between spoken and written units. Initially GL was developed and found effective in training children at risk of reading disorders in Finland. Today GL training has been shown to support learning decoding skills among children independent of whether they face difficulties resulting from educational, social, or biological reasons., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Juhani Lyytinen, Semrud-Clikeman, Li, Pugh and Richardson.)

Developmental dyslexia is a specific learning disorder with impairments in reading and spelling acquisition. Apart from literacy problems, dyslexics show inefficient speech encoding and deficient novel word learning, with underlying problems in phonological processing and learning. These problems have been suggested to be related to deficient specialization of the left hemisphere for language processing. To examine this possibility, we tracked with magnetoencephalography (MEG) the activation of the bilateral temporal cortices during formation of neural memory traces for new spoken word forms in 7-8-year-old children with high familial dyslexia risk and in controls. The at-risk children improved equally to their peers in overt repetition of recurring new word forms, but were poorer in explicit recognition of the recurring word forms. Both groups showed reduced activation for the recurring word forms 400-1200 ms after word onset in the right auditory cortex, replicating the results of our previous study on typically developing children (Nora et al., 2017, Children show right-lateralized effects of spoken word-form learning. PLoS ONE 12(2): e0171034). However, only the control group consistently showed a similar reduction of activation for recurring word forms in the left temporal areas. The results highlight the importance of left-hemispheric phonological processing for efficient phonological representations and its disruption in dyslexia., (Copyright © 2021. Published by Elsevier Inc.)

This paper reviews the observations of the Jyväskylä Longitudinal Study of Dyslexia (JLD). The JLD is a prospective family risk study in which the development of children with familial risk for dyslexia (N = 108) due to parental dyslexia and controls without dyslexia risk (N = 92) were followed from birth to adulthood. The JLD revealed that the likelihood of at-risk children performing poorly in reading and spelling tasks was fourfold compared to the controls. Auditory insensitivity of newborns observed during the first week of life using brain event-related potentials (ERPs) was shown to be the first precursor of dyslexia. ERPs measured at six months of age related to phoneme length identification differentiated the family risk group from the control group and predicted reading speed until the age of 14 years. Early oral language skills, phonological processing skills, rapid automatized naming, and letter knowledge differentiated the groups from ages 2.5-3.5 years onwards and predicted dyslexia and reading development, including reading comprehension, until adolescence. The home environment, a child's interest in reading, and task avoidance were not different in the risk group but were found to be additional predictors of reading development. Based on the JLD findings, preventive and intervention methods utilizing the association learning approach have been developed.

Pinyin is an alphabetic script that denotes pronunciations of Chinese characters. Studies have shown that Pinyin instruction enhances both phonological awareness (e.g., Shu et al., Developmental Science, 2008, 11, 171-181) and character reading (e.g., Lin et al., Psychological Science, 2010, 21, 1117-1122) in Chinese children. In the present study, we provided a 3-week Pinyin intervention with a computer-based Pinyin GraphoGame to disadvantaged migrant children with poor Pinyin skills. A total of 252 first graders who were children of migrant workers in a large Chinese city were assessed to identify poor Pinyin readers. Fifty-six 7-year-old children with poor Pinyin skills were selected and randomly divided into a training group and a control group, with 28 children in each group. The training group played the Pinyin GraphoGame for 3 weeks, while the control group received school instruction only during the same period. Results showed that the children in the training group outperformed their peers in the control group on Pinyin reading accuracy and fluency, onset-rime and phonemic awareness, and character reading. These results suggest that the Pinyin GraphoGame may be a cost-effective method to enhance Pinyin and literacy outcomes for underprivileged children in China., (© 2020 John Wiley & Sons Ltd.)

Background: The association between use of menopausal hormone therapy and risk of cutaneous melanoma is highly debated. We investigated the issue in a Finnish nationwide cohort of women ages 50 years or older., Methods: All women who had purchased hormone therapy between 1994 and 2007 were identified from the national Medical Reimbursement Registry and linked to the Finnish Cancer Registry. We calculated standardized incidence ratios (SIR) to compare incidence of cutaneous melanoma among hormone therapy users with that of the general population., Results: During a mean follow-up of 15.6 years, 1,695 incident cutaneous melanoma cases were identified among 293,570 women who had used hormone therapy for at least 6 months. The SIRs for women who used unopposed estrogen therapy and combined estrogen-progestin therapy (EPT) for 6 to 59 months were 1.20 [95% confidence interval (CI), 1.06-1.35] and 1.00 (95% CI, 0.87-1.14; P heterogeneity = 0.04). The SIRs for women who used estrogen therapy and EPT for at least 60 months were 1.37 (95% CI, 1.22-1.52) and 1.23 (95% CI, 1.13-1.34; P heterogeneity = 0.15). We did not find significant differences between oral and transdermal administrations, nor between doses of estrogens., Conclusions: Use of hormone therapy, especially estrogen therapy, was associated with an increased risk of cutaneous melanoma. EPT use of less than 5 years was not associated with an increased risk of cutaneous melanoma., Impact: Our results add to the growing body of epidemiologic evidence that the use of unopposed estrogens in menopause increases the risk of cutaneous melanoma, while the addition of progestins might counteract the detrimental effect., (©2019 American Association for Cancer Research.)

Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562-3468). We observed a genome-wide significant effect (p < 1 × 10 -8 ) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10 -9 ), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10 -8 ). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10 -8 ) and with all the cognitive traits tested (p = 3.07 × 10 -8 ), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10 -5 -10 -7 ]) and negatively associated with ADHD PRS (p ~ [10 -8 -10 -17 ]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.

Reading is an essential skill in modern societies, yet not all learners necessarily become proficient readers. Theoretical concepts (e.g., the orthographic depth hypothesis; the grain size theory) as well as empirical evidence suggest that certain orthographies are easier to learn than others. The present paper reviews the literature on orthographic transparency, morphological complexity, and syllabic complexity of alphabetic languages. These notions are elaborated to show that differences in reading acquisition reflect fundamental differences in the nature of the phonological recoding and reading strategies developing in response to the specific orthography to be learned. The present paper provides a narrative, cross-linguistic and integrated literature review, thereby contributing to the development of universal reading models and at the same time pointing out the important differences between orthographies at the more detailed level. Our review also yields suggestions to devise language-specific instruction and interventions for the development of the specific reading strategies required by the characteristics of the orthography being acquired.

India, a country with a population of more than 1.3 billion individuals, houses the world's second largest educational system. Despite this, 100 of millions of individuals in India are still illiterate. As English medium education sweeps the country, many are forced to learn in a language which is foreign to them. Those living in poverty further struggle to learn English as it tends to be a language which they have no prior exposure to and no support at home for. Low-quality schools and poor instructional methods further exacerbate the problem. Without access to quality education, these individuals continue to struggle and are ultimately never given the chance to break the cycle of poverty. The aim of this study was to determine whether GraphoLearn, a computer-assisted reading tool, could be used to support the English reading skills of struggling readers in India. Participants were 7-year-old, grade 3 students ( N = 30), who were attending an English-medium public school in Ahmedabad, India. English was not a native language for any of the students and all were reading at a level below that of Grade 1 despite having attended school for 2 years. Half of the students played GraphoLearn ( n = 16) while the other half played a control math game ( n = 14) for 20-30 min a day, over a period of 8 weeks. GraphoLearn led to significant improvements in children's letter-sound knowledge, a critical factor in early reading development. Overall, the study opens doors for GraphoLearn as a potential intervention to support struggling readers of English in India, including those who are learning a non-native language and coming from at-risk backgrounds.

Dyslexia is a neurobiological disorder impairing learning to read. Brain responses of infants at genetic risk for dyslexia are abnormal already at birth, and associations from infant speech perception to preschool cognitive skills and reading in early school years have been documented, but there are no studies showing predicting power until adolescence. Here we show that in at-risk infants, brain activation to pseudowords at left hemisphere predicts 44% of reading speed at 14 years, and even improves the prediction after taking into account neurocognitive preschool measures of letter naming, phonology, and verbal short-term memory. The association between infant brain responses and reading speed is mediated by preschool rapid automatized naming ability. Therefore, we suggest that rapid naming and reading speed could share a similar cognitive process of automatized access to lexicon via phonological representations, and brain activation to speech sounds in infancy probably acts as an index of deficient development of the same process., (Copyright © 2017. Published by Elsevier Ltd.)

This narrative review discusses quantitative indices measuring differences between alphabetic languages that are related to the process of word recognition. The specific orthography that a child is acquiring has been identified as a central element influencing reading acquisition and dyslexia. However, the development of reliable metrics to measure differences between language scripts hasn't received much attention so far. This paper therefore reviews metrics proposed in the literature for quantifying orthographic transparency, syllabic complexity, and morphological complexity of alphabetic languages. The review included searches of Web of Science, PubMed, PsychInfo, Google Scholar, and various online sources. Search terms pertained to orthographic transparency, morphological complexity, and syllabic complexity in relation to reading acquisition, and dyslexia. Although the predictive value of these metrics is promising, more research is needed to validate the value of the metrics discussed and to understand the 'developmental footprint' of orthographic transparency, morphological complexity, and syllabic complexity in the lexical organization and processing strategies.

Objectives: The role of postmenopausal hormone therapy (HT) in the incidence of acute coronary syndrome (ACS) has been studied extensively, but less is known of the impact of HT on the mortality risk due to an ACS., Study Design and Main Outcome Measures: We extracted from a population-based ACS register, FINAMI, 7258 postmenopausal women with the first ACS. These data were combined with HT use data from the National Drug Reimbursement Register; 625 patients (9%) had used various HT regimens. The death risks due to ACS before admission to hospital, 2-28, or 29-365days after the incident ACS were compared between HT users and non-users with logistic regression analyses., Results: In all follow-up time points, the ACS death risks in HT ever-users were smaller compared to non-users. Of women with HT ever use, 42% died within one year as compared with 52% of non-users (OR 0.62, p<0.001). Most deaths (84%) occurred within 28days after the ACS, and in this group 36% of women with ever use of HT (OR 0.73, p=0.002) and 30% of women with ≥5year HT use (OR 0.54, p<0.001) died as compared to 43% of the non-users. Age ≤60 or >60 years at the HT initiation was accompanied with similar reductions in ACS mortality risk., Conclusions: Postmenopausal HT use is accompanied with reduced mortality risk after primary ACS., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Study Question: Does the use of post-menopausal vaginal estradiol (VE) affect the mortality risk for coronary heart disease (CHD) and stroke., Summary Answer: The use of VE reduces the risk for cardiovascular mortality., What Is Known Already: A growing number of women use VE for post-menopausal genitourinary symptoms. Although this therapy is intended to have only local effects, estrogen is absorbed into the blood circulation and thus VE use may also have systemic effects., Study Design, Size, Duration: We studied a nationwide cohort in Finland 1994-2009 during which post-menopausal women (n = 195 756) initiated the use of VE (age [mean ± SD] 65.7 ± 10.9 years). Follow-up data gathered 1.4 million women-years and we assessed the mortality risk due to CHD (n= 9656) or stroke (n = 4294)., Participants/materials, Setting, Methods: The mortality risk in VE users was compared with that in the age-matched background population (standardized mortality ratio; [SMR]; 95% confidence interval) and related to various durations of exposure to VE (1 to ≤3, >3 to ≤5, >5 to ≤10 and >10 years)., Main Results and the Role of Chance: The use of VE was accompanied by decreases in the risk for CHD and stroke death. The risk reduction for CHD death was highest for >3 to ≤5 years exposure (SMR 0.64; 0.57-0.70) and for stroke for >5 to ≤10 years exposure (SMR 0.64; 0.57-0.72). The risk reductions for both CHD and stroke mortality were detected in all age groups with the highest risk reduction being in women aged 50-59 years (SMR 0.43; 0.19-0.88 and SMR 0.21; 0.06-0.58, respectively)., Limitations, Reasons for Caution: Our series lack a placebo arm and thus, may harbor a healthy woman bias. Moreover, data on clinical variables such as weight, smoking, blood pressure and family background were unobtainable for this study. Women using both VE and systemic hormone therapy (HT) were included in the comparator background population. This should not cause any significant error because the proportion of women using VE or other HT was modest (<10% in age-matched population) and because the use of systemic HT also reduces death risks in the same population. Our data cannot be directly applied for local regimens containing conjugated equine estrogens, because they are absorbed differently and may show effects that differ from those of estradiol., Wider Implications of the Findings: In 1000 women using VE for up to 10 years, a maximum of 24 fewer CHD deaths and 18 fewer stroke deaths is likely to occur., Study Funding/competing Interests: This work was supported by unrestricted grants from the Päivikki and Sakari Sohlberg Foundation, the Emil Aaltonen Foundation, the Finnish Medical Foundation, Finska Läkaresällskapet, the Orion Farmos Research Foundation, the Paavo Nurmi Foundation and a special governmental grant for health sciences research. The funding sources had no role in the study design, data handling or manuscript preparation. EPID Research is a company that performs financially supported studies for several pharmaceutical companies. Dr Korhonen, Dr Hoti and MSc Vattulainen, employed by Epid Research, report financial activities from several other pharmaceutical companies outside the submitted work. Dr Mikkola has been a speaker and/or received consulting fees from Mylan and Novo Nordisk. Dr Tuomikoski has been a speaker and/or received consulting fees from Orion and Mylan. The remaining authors report no conflict of interest., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Associative learning has been identified as one of several non-linguistic processes involved in reading acquisition. However, it has not been established whether it is an independent process that contributes to reading performance on its own or whether it is a process that is embedded in other linguistic skills (e.g., phonological awareness or phonological memory) and, therefore, contributing to reading performance indirectly. Research has shown that performance on tasks assessing associative learning, e.g., paired-associate learning (PAL) tasks, is lower in children with specific reading difficulties compared to typical readers. We explored the differential associations of two distinct verbal-visual PAL tasks (the Bala Bbala Graphogame, BBG, and a Foreign Language Learning Task, FLLT) with reading skills (word reading and pseudo-word decoding), controlling for phonological awareness, rapid naming, and letter and digit span in children at risk for reading disabilities and their typically developing peers. Our study sample consisted of 110 children living in rural Zambia, ranging in age from 7 to 18 years old (48.1% female). Multivariate analyses of covariance were used to explore the group differences in reading performance. Repeated-measures ANCOVA was used to examine children's learning across the PAL tasks. The differential relationships between both PAL tasks and reading performance were explored via structural equation modeling. The main result was that the children at risk for reading difficulties had lower performance on both PAL tasks. The BBG was a significant predictor for both word reading and pseudo-word decoding, whereas the FLLT-only for word reading. Performance on the FLLT partially mediated the association between phonological awareness and word reading. These results illustrate the partial independence of associative learning from other reading-related skills; the specifics of this relationship vary based on the type of PAL task administered.

Context: Current guidelines recommend annual discontinuation of postmenopausal hormone therapy (HT) to evaluate whether a woman could manage without the treatment. The impact of HT on cardiovascular health has been widely studied, but it is not known how the withdrawal of HT affects cardiovascular risk., Objective: We evaluated the risk of cardiac or stroke death after the discontinuation of HT. Design, Patients, Interventions, and Main Outcome Measures: Altogether 332 202 Finnish women discontinuing HT between 1994 and 2009 (data from National Reimbursement register) were followed up from the discontinuation date to death due to cardiac cause (n = 3177) or stroke (n = 1952), or to the end of 2009. The deaths, retrieved from the national Cause of Death Register, were compared with the expected number of deaths in the age-standardized background population. In a subanalysis we also compared HT stoppers with HT users., Results: Within the first posttreatment year, the risk of cardiac death was significantly elevated (standardized mortality ratio; 95% confidence interval 1.26; 1.16-1.37), whereas follow-up for longer than 1 year was accompanied with a reduction (0.75; 0.72-0.78). The risk of stroke death in the first posttreatment year was increased (1.63; 1.47-1.79), but follow-up for longer than 1 year was accompanied with a reduced risk (0.89; 0.85-0.94). The cardiac (2.30; 2.12-2.50) and stroke (2.52; 2.28-2.77) death risk elevations were even higher when compared with HT users. In women who discontinued HT at age younger than 60 years, but not in women aged 60 years or older, the cardiac mortality risk was elevated (1.94; 1.51-2.48)., Conclusions: Increased cardiovascular death risks question the safety of annual HT discontinuation practice to evaluate whether a woman could manage without HT.

Data on the possible impact of postmenopausal hormone therapy (HT) on the incidence of rare primary fallopian tube carcinoma (PFTC) are scarce. Therefore, we conducted a nationwide case-control study analyzing the association between the use of different HTs and PFTC. All women aged 50 years or older with an incident PFTC (n = 360) during 1995-2007 were identified from the Finnish Cancer Registry. For each case of PFTC, ten age- and place of residence-matched controls were selected from the Finnish National Population Register, which also provided information on parity. Data on HT purchases were received from the Prescription Register, and data on hysterectomies and sterilizations from the National Care Register. Controls with a salpingectomy before the PFTC diagnosis of the respective case were excluded. The PFTC risk in relation to different HTs was estimated with a conditional logistic regression model, adjusted for parity, age at last delivery, hysterectomy and sterilization. The use for five years or more of estradiol combined with levonorgestrel-releasing-intrauterine system (odds ratio 2.84, 95% confidence interval 1.10-7.38) and sequential estradiol-progestin therapy (EPT; 3.37; 2.23-5.08) were both linked with increases in the risk of PFTC, while the risk with use of estradiol-only therapy or continuous EPT was not statistically significantly increased. The OR for the use of tibolone for one year or more was 1.56 (0.55-4.41). The use of HT is related to an increased risk of PFTC, particularly when a progestin component is intrauterine or systemic progestin is given in sequential manner., (© 2015 UICC.)

This study focuses on the stability of dyslexia status from Grade 2 to Grade 8 in four groups: (a) no dyslexia in either grade (no-dyslexia, n = 127); (b) no dyslexia in Grade 2 but dyslexia in Grade 8 (late-emerging, n = 18); (c) dyslexia in Grade 2 but not in Grade 8 (resolving, n = 15); and (d) dyslexia in both grades (persistent-dyslexia, n = 22). We examined group differences from age 3.5 to age 14 in (a) reading, vocabulary, phonology, letter knowledge, rapid naming, IQ, verbal memory; (b) familial and environmental risk and supportive factors; and (c) parental skills in reading, phonology, rapid naming, verbal memory, and vocabulary. Our findings showed group differences both in reading and cognitive skills of children as well as their parents. Parental education, book-reading frequency, and children's IQ, however, did not differentiate the groups. The children in the persistent-dyslexia group exhibited widespread language and cognitive deficits across development. Those in the resolving group had problems in language and cognitive skills only prior to school entry. In the late-emerging group, children showed clearly compromised rapid naming. Additionally, their parents had the most severe difficulties in rapid naming, a finding that suggests strong genetic liability. The findings show instability in the diagnosis of dyslexia. The members of the late-emerging group did not have a distinct early cognitive profile, so late-emerging dyslexia appears difficult to predict. Indeed, these children are at risk of not being identified and not receiving required support. This study suggests the need for continued monitoring of children's progress in literacy after the early school years.

Objective: Data on the health benefits and risks of postmenopausal hormone therapy (HT) are derived mainly from the use of conjugated equine estrogens. Estradiol-based regimens may have a different risk-benefit profile. We evaluated the risk of death caused by coronary heart disease (CHD), stroke, or any disease among users of estradiol-based HT regimens in a nationwide study in Finland., Methods: A total of 489,105 women who used HT from 1994 to 2009 (3.3 million HT exposure years), as indicated in the nationwide reimbursement register and the national Cause of Death Register, were followed. A total of 28,734 HT users died during follow-up; among the deaths, 3,843 were caused by CHD and 2,464 were caused by stroke. Mortality risk in HT users with varying duration of exposure (≤1 y, >1 to 3 y, >3 to 5 y, >5 to 10 y, or >10 y) was compared with that in an age-matched background population., Results: Risk of CHD death was significantly reduced by 18% to 54% in HT users and was positively related to HT exposure time. Risk of stroke death was also reduced by 18% to 39%, but this reduction was not clearly related to HT exposure time. Risk of all-cause mortality was reduced in HT users by 12% to 38%, almost in linear relationship with duration of exposure. All these risk reductions were comparable in women initiating HT before age 60 years and women initiating HT at age 60 years or older., Conclusions: In absolute terms, the risk reductions mean 19 fewer CHD deaths and 7 fewer stroke deaths per 1,000 women using any HT for at least 10 years.

Objective: The Women's Health Initiative (WHI) study clarified the indications and contraindications for postmenopausal hormone therapy (HT). We studied the impact of the WHI results on the risk of fatal stroke in HT users in Finland., Study Design: Retrospective analysis setting: Nationwide registers on postmenopausal HT use and causes of death between 1995 and 2009., Population: Women ≥40 years (n=290,272) using systemic estradiol-based postmenopausal HT., Methods: Follow-up started from the first HT purchase during the pre-WHI era (1995-2001) and post-WHI era (2002-2009)., Main Outcome Measures: Stroke deaths in HT users were compared with that in the age-matched background population and expressed as standardized mortality ratio (SMR) with 95% confidence intervals., Results: Overall, 311 HT users died due to stroke. The exposure to HT ≤1 year was associated with a similarly reduced 22% (0.67-0.91) risk of stroke death in the pre-WHI era and in the post-WHI era 27% (0.55-0.94). The risk reductions for HT exposure of 1-8 years in the pre-WHI era (47%, 0.42-0.65) did not differ from that in the post-WHI era (32%, 0.48-0.94). The discontinuation of HT was accompanied by a significant 33% (1.02-1.72) increase in stroke death risk in the pre-WHI era and a non-significant 32% (0.84-1.99) increase in the post-WHI era within the first post-treatment year, but no longer after 1-8 years., Conclusions: The change in prescribing policy after the WHI study did not affect the risk of fatal stroke in Finnish HT users., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Genetic studies of complex traits have become increasingly successful as progress is made in next-generation sequencing. We aimed at discovering single nucleotide variation present in known and new candidate genes for developmental dyslexia: CYP19A1, DCDC2, DIP2A, DYX1C1, GCFC2 (also known as C2orf3), KIAA0319, MRPL19, PCNT, PRMT2, ROBO1 and S100B. We used next-generation sequencing to identify single-nucleotide polymorphisms in the exons of these 11 genes in pools of 100 DNA samples of Finnish individuals with developmental dyslexia. Subsequent individual genotyping of those 100 individuals, and additional cases and controls from the Finnish and German populations, validated 92 out of 111 different single-nucleotide variants. A nonsynonymous polymorphism in DCDC2 (corrected P = 0.002) and a noncoding variant in S100B (corrected P = 0.016) showed a significant association with spelling performance in families of German origin. No significant association was found for the variants neither in the Finnish case-control sample set nor in the Finnish family sample set. Our findings further strengthen the role of DCDC2 and implicate S100B, in the biology of reading and spelling.

GraphoGame (GG) is originally a technology-based intervention method for supporting children with reading difficulties. It is now known that children who face problems in reading acquisition have difficulties in learning to differentiate and manipulate speech sounds and consequently, in connecting these sounds to corresponding letters. GG was developed to provide intensive training in matching speech sounds and larger units of speech to their written counterparts. GG has been shown to benefit children with reading difficulties and the game is now available for all Finnish school children for literacy support. Presently millions of children in Africa fail to learn to read despite years of primary school education. As many African languages have transparent writing systems similar in structure to Finnish, it was hypothesized that GG-based training of letter-sound correspondences could also be effective in supporting children's learning in African countries. In this article we will describe how GG has been developed from a Finnish dyslexia prevention game to an intervention method that can be used not only to improve children's reading performance but also to raise teachers' and parents' awareness of the development of reading skill and effective reading instruction methods. We will also provide an overview of the GG activities in Zambia, Kenya, Tanzania, and Namibia, and the potential to promote education for all with a combination of scientific research and mobile learning.

Over two decades of Finnish research, monitoring children born with risk for dyslexia has been carried out in the Jyväskylä Longitudinal Study of Dyslexia (JLD). Two hundred children, half at risk, have been assessed from birth to puberty on hundreds of measures. The aims were to identify measures of prediction of later reading difficulty and to instigate appropriate and earliest diagnosis and intervention. We can identify at-risk children from newborn electroencephalographic brain recordings (Guttorm et al., J Neural Transm 110:1059-1074, 2003). Predictors are also apparent from late-talking infants who have familial background of dyslexia (Lyytinen and Lyytinen, Appl Psycolinguistics 25:397-411, 2004). The earliest easy-to-use predictive measure to identify children who need help to avoid difficulties in learning to read is letter knowledge (Lyytinen et al., Merrill-Palmer Q 52:514-546, 2006). In response, a purpose-engineered computer game, GraphoGame ™ , provides an effective intervention tool (Lyytinen et al., Scand J Psychol 50:668-675, 2009). In doubling as a research instrument, GraphoGame provides bespoke intervention/reading instruction for typical/atypically developing children. Used extensively throughout Finland, GraphoGame is now crossing the developed and developing world to assist children, irrespective of the cause (environmental or genetic) of their failing to learn to read (Ojanen et al., Front Psychol 6(671):1-13, 2015).

Hormone therapy is the most effective treatment for sweating and hot flashes, which are the most common symptoms of the menopause. The initiation of therapy for a healthy female of 50 to 59 years usually entails more health benefits than adverse effects, and there is no absolute upper limit for the duration of the treatment. It remains to be evaluated yearly whether the need or prerequisites for continuation of the treatment still exist. If the use of hormone therapy is not desired, alleviation of hot flashes and sweating can be attempted with life style modifications and other remedies.

Computer-assisted training of Finnish phonemic length was conducted with 7-year-old Russian-speaking second-language learners of Finnish. Phonemic length plays a different role in these two languages. The training included game activities with two- and three-syllable word and pseudo-word minimal pairs with prototypical vowel durations. The lowest accuracy scores were recorded for two-syllable words. Accuracy scores were higher for the minimal pairs with larger rather than smaller differences in duration. Accuracy scores were lower for long duration than for short duration. The ability to identify quantity degree was generalized to stimuli used in the identification test in two of the children. Ideas for improving the game are introduced.

Specific reading disability, dyslexia, is a prevalent and heritable disorder impairing reading acquisition characterized by a phonological deficit. However, the underlying mechanism of how the impaired phonological processing mediates resulting dyslexia or reading disabilities remains still unclear. Using ERPs we studied speech sound processing of 30 dyslexic children with familial risk for dyslexia, 51 typically reading children with familial risk for dyslexia, and 58 typically reading control children. We found enhanced brain responses to shortening of a phonemic length in pseudo-words (/at:a/ vs. /ata/) in dyslexic children with familial risk as compared to other groups. The enhanced brain responses were associated with better performance in behavioral phonemic length discrimination task, as well as with better reading and writing accuracy. Source analyses revealed that the brain responses of sub-group of dyslexic children with largest responses originated from a more posterior area of the right temporal cortex as compared to the responses of the other participants. This is the first electrophysiological evidence for a possible compensatory speech perception mechanism in dyslexia. The best readers within the dyslexic group have probably developed alternative strategies which employ compensatory mechanisms substituting their possible earlier deficit in phonological processing and might therefore be able to perform better in phonemic length discrimination and reading and writing accuracy tasks. However, we speculate that for reading fluency compensatory mechanisms are not that easily built and dyslexic children remain slow readers during their adult life., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: To assess whether coronary heart disease mortality in Finnish hormone therapy (HT) users differed before and after 2002 when the Women's Health Initiative study was published., Methods: The risks of coronary heart disease death in HT users in relation to the age-matched background population were compared between the pre- (1995-2001) and post- (2002-2009) Women's Health Initiative eras. We used a nationwide register on HT (ie, estradiol with or without progestin) reimbursement and linked them to causes of death in 290,272 women aged 40 years or older., Results: Exposure to HT for 1 year or less was accompanied by a 29% reduction (0.71; 0.63-0.80; three per 10,000 fewer deaths) and an exposure of 1-8 years with a 43% reduction (0.57; 0.48-0.66; three per 10,000 fewer deaths) in the risk of coronary heart disease death in the pre-Women's Health Initiative era. In the post-Women's Health Initiative era, HT use of 1 year or less was associated with an 18% reduction (0.82; 0.76-1.00; one per 10,000 fewer deaths) and an exposure of 1-8 years with a 54% reduction (0.46; 0.32-0.64; two per 10,000 fewer deaths) in coronary heart disease mortality. Discontinuation of HT was associated with an increased risk of cardiac death of 42% (1.42; 1.17-1.71; seven per 10,000 extra deaths) in the pre-Women's Health Initiative era and 31% (1.31; 0.92-1.82; two per 10,000 extra deaths) in the post-Women's Health Initiative era during the first posttreatment year. This risk increase vanished in further follow-up during both eras., Conclusion: Changes in HT use after the Women's Health Initiative failed to affect coronary heart disease mortality of HT users in this nationwide study.

Dyslexia is one of the most common childhood disorders with a prevalence of around 5-10% in school-age children. Although an important genetic component is known to have a role in the aetiology of dyslexia, we are far from understanding the molecular mechanisms leading to the disorder. Several candidate genes have been implicated in dyslexia, including DYX1C1, DCDC2, KIAA0319, and the MRPL19/C2ORF3 locus, each with reports of both positive and no replications. We generated a European cross-linguistic sample of school-age children - the NeuroDys cohort - that includes more than 900 individuals with dyslexia, sampled with homogenous inclusion criteria across eight European countries, and a comparable number of controls. Here, we describe association analysis of the dyslexia candidate genes/locus in the NeuroDys cohort. We performed both case-control and quantitative association analyses of single markers and haplotypes previously reported to be dyslexia-associated. Although we observed association signals in samples from single countries, we did not find any marker or haplotype that was significantly associated with either case-control status or quantitative measurements of word-reading or spelling in the meta-analysis of all eight countries combined. Like in other neurocognitive disorders, our findings underline the need for larger sample sizes to validate possibly weak genetic effects.

Postmenopausal hormone therapy (HT) associates with an increased risk of ovarian cancer, but its' influence on tumor histology is not as well known. Therefore, we evaluated the effect of various types of HT on the risk of epithelial ovarian cancer by histological subtype. All Finnish women diagnosed with ovarian cancer (n = 3,958) aged over 50 during 1995-2007 were identified from the Finnish Cancer Registry. For each case, three controls, matched for age and place of residence, were recruited from the Finnish National Population Register, which also provided data on parity and ages at deliveries. After exclusion of controls with oophorectomy, 11,325 controls remained. The prescription register provided HT use from age 50. Odds ratios (OR) for different HTs were estimated by conditional logistic regression: adjusted for parity, ages at deliveries and hysterectomy. Estradiol-only therapy use for 5 years or more associated with an increased risk (OR 1.45; 95% confidence interval 1.20-1.75) of a serous subtype, but with a decreased risk of mucinous subtype (0.35; 0.19-0.67). Use of sequential estradiol-progestin therapy (EPT) for 5 years or more associated with an increase in overall ovarian cancer risk (1.35; 1.20-1.63) and with an increase in the endometrioid subtype (1.88; 1.24-2.86) particularly. Continuous EPT, estradiol + levonorgestrel-releasing intrauterine system or tibolone had no effect on overall ovarian cancer risk. In conclusion, only sequential EPT use for 5 years or more associates with an increased risk of overall ovarian cancer. Furthermore, HT regimens differ significantly in their association with various histological types of ovarian cancer., (© 2013 UICC.)

Purpose: The authors investigated the importance of phonemic length discrimination ability on reading and spelling skills among children with reading disabilities and familial risk for dyslexia and among children with typical reading skills, as well as the role of prereading skills in reading and spelling development in children with reading disabilities., Method: Finnish children with reading disabilities and discrimination problems (RDDP, n = 13), children with reading disabilities and typical discrimination abilities (RDTD, n = 27), and children with typical reading skills (TR, n = 140) were assessed between the ages of 1 and 6.5 years for language, phonological awareness, IQ, verbal memory, and rapid automatized naming. IQ, discrimination ability, and reading and spelling skills were assessed in the second grade. Statistical differences were examined at the group level., Results: The RDDP group was poorer in spelling accuracy compared with the other groups. The RDDP group's prereading skills were poorer than those of the RDTD group. In regression analyses, the RDDP group's poor spelling skills were partially explained by their discrimination ability., Conclusion: Prereading skills are connected to poor reading skills, but phonemic length discrimination ability plays a critical role in spelling accuracy problems among children with reading disabilities and with familial risk for dyslexia.

Background:  The relationship between phoneme awareness, rapid automatized naming (RAN), verbal short-term/working memory (ST/WM) and diagnostic category is investigated in control and dyslexic children, and the extent to which this depends on orthographic complexity., Methods: General cognitive, phonological and literacy skills were tested in 1,138 control and 1,114 dyslexic children speaking six different languages spanning a large range of orthographic complexity (Finnish, Hungarian, German, Dutch, French, English)., Results: Phoneme deletion and RAN were strong concurrent predictors of developmental dyslexia, while verbal ST/WM and general verbal abilities played a comparatively minor role. In logistic regression models, more participants were classified correctly when orthography was more complex. The impact of phoneme deletion and RAN-digits was stronger in complex than in less complex orthographies., Conclusions: Findings are largely consistent with the literature on predictors of dyslexia and literacy skills, while uniquely demonstrating how orthographic complexity exacerbates some symptoms of dyslexia., (© 2012 The Authors. Journal of Child Psychology and Psychiatry © 2012 Association for Child and Adolescent Mental Health.)

Objective: While previous data link the use of postmenopausal hormone therapy to an increased risk for ovarian cancer, little is known about the impact of various progestins, modes or routes of administration of hormone therapy for this risk. In this nationwide study, we compared relations between different estradiol-progestin (EPT) formulations and epithelial ovarian cancer risk., Methods: All Finnish women over 50 years using EPT for at least 6 months (224 015 women with 602 ovarian cancers) during 1994-2006 were identified from the reimbursement register. The incidence of ovarian cancer in EPT users was compared to that in the age-matched background population by means of observed to expected ratio (standardized incidence ratio, SIR)., Results: Ovarian cancer risk was not elevated for EPT use of < 5 years but it was elevated for EPT use of ≥5 years (SIR 1.21, 95% confidence interval (CI) 1.06-1.37). Medroxyprogesterone acetate and norethisterone acetate as components of EPT were associated with similar risks for use for ≥ 5 years (SIR 1.26, 95% CI 0.94-1.64 and SIR 1.42, 95% CI 1.11-1.77, respectively). The risk did not differ between sequential or continuous EPT regimens or between oral or transdermal EPT formulations. The risk elevation for EPT use for ≥ 5 years was seen only for serous (SIR 1.56; 95% CI 1.33-1.80) and mixed cancers (SIR 1.54; 95% CI 1.22-1.91), whereas the risk for mucinous cancer was decreased (SIR 0.47; 95% CI 0.22-0.86)., Conclusion: The elevated risk of non-mucinous ovarian cancer in users of EPT ≥ 5 years does not depend on progestin type, mode or route of administration of EPT.

This longitudinal study examined early cognitive risk and protective factors for Grade 2 reading disability (RD). We first examined the reading outcome of 198 children in four developmental cognitive subgroups that were identified in our previous analysis: dysfluent trajectory, declining trajectory, unexpected trajectory and typical trajectory. We found that RD was unevenly distributed among the subgroups, although children with RD were found in all subgroups. A majority of the children with RD had familial risk for dyslexia. Second, we examined in what respect children with similar early cognitive development but different RD outcome differ from each other in cognitive skills, task-focused behaviour and print exposure. The comparison of the groups with high cognitive risk but different RD outcome showed significant differences in phonological skills, in the amount of shared reading and in task-focused behaviour. Children who ended up with RD despite low early cognitive risk had poorer cognitive skills, more task avoidance and they were reading less than children without RD and low cognitive risk. In summary, lack of task avoidance seemed to act as a protective factor, which underlines the importance of keeping children interested in school work and reading., (Copyright © 2013 John Wiley & Sons, Ltd.)

This study addresses how to validate the rationale of group component analysis (CA) for blind source separation through estimating the number of sources in each individual EEG dataset via model order selection. Control children, typically reading children with risk for reading disability (RD), and children with RD participated in the experiment. Passive oddball paradigm was used for eliciting mismatch negativity during EEG data collection. Data were cleaned by two digital filters with pass bands of 1-30 Hz and 1-15 Hz and a wavelet filter with the pass band narrower than 1-12 Hz. Three model order selection methods were used to estimate the number of sources in each filtered EEG dataset. Under the filter with the pass band of 1-30 Hz, the numbers of sources were very similar among different individual EEG datasets and the group ICA would be suggested; regarding the other two filters with much narrower pass bands, the numbers of sources were relatively diverse, and then, applying group ICA would not be appropriate. Hence, before group ICA is performed, its rationale can be logically validated by the estimated number of sources in EEG data through model order selection., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Identifying children at risk for reading problems or dyslexia at kindergarten age could improve support for beginning readers. Brain event-related potentials (ERPs) were measured for temporally complex pseudowords and corresponding non-speech stimuli from 6.5-year-old children who participated in behavioral literacy tests again at 9 years in the second grade. Children who had reading problems at school age had larger N250 responses to speech and non-speech stimuli particularly at the left hemisphere. The brain responses also correlated with reading skills. The results suggest that atypical auditory and speech processing are a neural-level risk factor for future reading problems. [Supplementary material is available for this article. Go to the publisher's online edition of Developmental Neuropsychology for the following free supplemental resources: Sound files used in the experiments. Three speech sounds and corresponding non-speech sounds with short, intermediate, and long gaps].

Sensitivity to print is characterized by a left occipito-temporal negativity to words in the event-related potential N1. This sensitivity is modulated by reading skills and may thus represent a neural marker of reading competence. Here we studied the development of the N1 in regular and poor readers from preschool age to school age to test whether the amplitude of the N1 predicts children's reading outcomes. Our results suggest a predictive value of the print-sensitive negativity over the right hemisphere. Whether this N1 may serve as a biomarker to improve prognosis in preliterate children should be clarified in future studies.

Through exploiting temporal, spectral, time-frequency representations, and spatial properties of mismatch negativity (MMN) simultaneously, this study extracts a multi-domain feature of MMN mainly using non-negative tensor factorization. In our experiment, the peak amplitude of MMN between children with reading disability and children with attention deficit was not significantly different, whereas the new feature of MMN significantly discriminated the two groups of children. This is because the feature was derived from multi-domain information with significant reduction of the heterogeneous effect of datasets.

The aim of this study was to evaluate the association of postmenopausal estradiol-progestagen therapy (EPT) with the risk for precancerous lesions, squamous cell carcinoma and adenocarcinoma of the uterine cervix. All Finnish women who had used EPT in 1994-2008 for at least 6 months (n = 243,857) at the age of 50 years or more were identified from the national Medical Reimbursement Registry and linked to the Finnish Cancer Registry. The incidence of cervical precancerous or cancerous lesions among EPT users was compared to that in the background population. There were 210 EPT users with squamous lesions (178 with precancerous and 32 with cancer) and 79 EPT users with glandular lesions (14 precancerous and 65 adenocarcinomas). The ever use of EPT did not associate with the incidence of precancerous lesions, but the risk for squamous cell carcinoma decreased (standardized incidence ratio 0.41; 95% confidence interval 0.28-0.58) and that for adenocarcinoma increased (1.31; 1.01-1.67). After the use of EPT for 5 years, the risk for squamous cell carcinoma decreased (0.34; 0.16-0.65), and the risk for adenocarcinomas increased (1.83; 1.24-2.59). The prolonged use of EPT is associated with the occurrence of cervical malignancies. If the association would be a causal one, the use for 5+ years among 10,000 women followed for 10 years would mean about two to three fewer cases of cervical squamous cell carcinoma but about two extra cases with adenocarcinoma., (Copyright © 2011 UICC.)

Objective: Primary fallopian tube carcinoma (PFTC) is a rare malignancy and only sparse data exist on its possible association with postmenopausal hormone therapy (HT). We therefore studied this association in a nationwide cohort of Finnish HT users., Methods: All women> 50 years using systemic estradiol-only therapy (ET) (n=117,820 hysterectomized women) or estradiol-progestin therapy (EPT) (n=247,781 nonhysterectomized women) for ≥ 6 months during 1994-2008 were identified from the national medical reimbursement register. The incidence of PFTC in HT users was compared to that in the comparable background population (standardized incidence ratio, SIR, with 95% confidence interval, CI)., Results: A total of 160 cases of PFTC were encountered in users of ET (n=34) or EPT (n=126). The use of EPT ≥ 5 years was accompanied by an increased risk for PFTC (SIR 2.15; 95% CI 1.66-2.72). The SIR increased further to 3.36 (95% CI 2.02-5.24) when EPT use lasted ≥ 10 years. The EPT-related risk for PFTC was restricted to the sequential EPT and it was not seen for continuous EPT. Two leading progestins in EPT, norethisterone acetate and medroxyprogesterone acetate, associated with comparable risk elevations. ET use was not associated with the risk for PFTC., Conclusions: The long-term, sequential use of EPT associates with an increased risk for PFTC. In absolute terms, 4 additional cases of PFTC would be detected in 10-year follow-up of 10,000 women who have used EPT for at least 5 years., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Inspired by the localization, on 15q21.2 of the CYP19A1 gene in the linkage region of speech and language disorders, and a rare translocation in a dyslexic individual that was brought to our attention, we conducted a series of studies on the properties of CYP19A1 as a candidate gene for dyslexia and related conditions. The aromatase enzyme is a member of the cytochrome P450 super family, and it serves several key functions: it catalyzes the conversion of androgens into estrogens; during early mammalian development it controls the differentiation of specific brain areas (e.g. local estrogen synthesis in the hippocampus regulates synaptic plasticity and axonal growth); it is involved in sexual differentiation of the brain; and in songbirds and teleost fishes, it regulates vocalization. Our results suggest that variations in CYP19A1 are associated with dyslexia as a categorical trait and with quantitative measures of language and speech, such as reading, vocabulary, phonological processing and oral motor skills. Variations near the vicinity of its brain promoter region altered transcription factor binding, suggesting a regulatory role in CYP19A1 expression. CYP19A1 expression in human brain correlated with the expression of dyslexia susceptibility genes such as DYX1C1 and ROBO1. Aromatase-deficient mice displayed increased cortical neuronal density and occasional cortical heterotopias, also observed in Robo1-/- mice and human dyslexic brains, respectively. An aromatase inhibitor reduced dendritic growth in cultured rat neurons. From this broad set of evidence, we propose CYP19A1 as a candidate gene for human cognitive functions implicated in reading, speech and language.

This study aimed at determining whether an intervention game developed for strengthening phonological awareness has a remediating effect on reading skills and central auditory processing in 6-year-old preschool children with difficulties in reading-related skills. After a 3-hour training only, these children made a greater progress in reading-related skills than did their matched controls who did mathematical exercises following comparable training format. Furthermore, the results suggest that this brief intervention might be beneficial in modulating the neural basis of phonetic discrimination as an enhanced speech-elicited mismatch negativity (MMN) was seen in the intervention group, indicating improved cortical discrimination accuracy. Moreover, the amplitude increase of the vowel-elicited MMN significantly correlated with the improvement in some of the reading-skill related test scores. The results, albeit obtained with a relatively small sample, are encouraging, suggesting that reading-related skills can be improved even by a very short intervention and that the training effects are reflected in brain activity. However, studies with larger samples and different subgroups of children are needed to confirm the present results and to determine how children with different dyslexia subtypes benefit from the intervention., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The authors conducted a nationwide cohort study to evaluate the association between postmenopausal hormone therapy and meningioma incidence in Finland. All women who had used hormone therapy at least for 6 months at the age of 50 years or older during 1994-2009 were included. Women who had used postmenopausal hormone therapy were identified from the medical reimbursement register of the Social Insurance Institution (131,480 estradiol users and 131,248 estradiol-progestin users), and meningioma cases were identified from the Finnish Cancer Registry. During the average 9 years of follow-up, 289 estradiol users and 196 estradiol-progestin users were diagnosed with meningioma. Ever use of estradiol-only therapy was associated with an increased risk of meningioma (standardized incidence ratio = 1.29, 95% confidence interval: 1.15, 1.44). Among women who had been using estradiol-only therapy for at least 3 years, the incidence of meningioma was 1.40-fold higher (95% confidence interval: 1.18, 1.64; P < 0.001) than in the background population. In contrast, this risk was not increased in users of combination therapy (standardized incidence ratio = 0.93, 95% confidence interval: 0.80, 1.06). There was no difference in risk between continuous and sequential use of hormone therapy. Estradiol-only therapy was accompanied with a slightly increased risk of meningioma.

Family history and poor preliteracy skills (referred to here as familial and behavioral risk, respectively) are critical predictors of developmental dyslexia. This study systematically investigated the independent contribution of familial and behavioral risks on brain structures, which had not been explored in past studies. We also examined the differential effects of maternal versus paternal history on brain morphometry, and familial risk dimensionally versus categorically, which were also novel aspects of the study. We assessed 51 children (5 to 6 years of age) with varying degrees of familial and behavioral risks for developmental dyslexia and examined associations with brain morphometry. We found that greater maternal history of reading disability was associated with smaller bilateral prefrontal and parieto-temporal gray, but not white matter volumes. Regressing out behavioral risk, socioeconomic status, and maternal education and other confounds did not change the results. No such relationship was observed for paternal reading history and behavioral risk. Results of cortical surface area and thickness further showed that there was a significant negative relationship between cortical surface area (but not thickness) and greater severity of maternal history, in particular within the left inferior parietal lobule, suggesting prenatal influence of maternal history on children's brain morphometry. The results suggested greater maternal, possibly prenatal, influence on language-related brain structures. These results help to guide future neuroimaging research focusing on environmental and genetic influences and provide new information that may help predict which child will develop dyslexia in the future., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Introduction: In Jyväskylä Longitudinal Study of Dyslexia, we have investigated neurocognitive processes related to phonology and other risk factors of later reading problems. Here we review studies in which we have investigated whether dyslexic children with familial risk background would show atypical auditory/speech processing at birth, at six months and later before school and at school age as measured by brain event-related potentials (ERPs), and how infant ERPs are related to later pre-reading cognitive skills and literacy outcome., Patients and Methods: One half of the children came from families with at least one dyslexic parent (the at-risk group), while the other half belonged to the control group without any familial background of dyslexia., Results: Early ERPs were correlated to kindergarten age phonological processing and letter-naming skills as well as phoneme duration perception, reading and writing skills at school age. The correlations were, in general, more consistent among at-risk children. Those at-risk children who became poor readers also differed from typical readers in the infant ERP measures at the group level. ERPs measured before school and at the 3rd grade also differed between dyslexic and typical readers. Further, speech perception at behavioural level differed between dyslexic and typical readers, but not in all dyslexic readers., Conclusions: These findings suggest persisting developmental differences in the organization of the neural networks sub-serving auditory and speech perception, with cascading effects on later reading related skills, in children with familial background for dyslexia. However, atypical auditory/speech processing is not likely a sufficient reason by itself for dyslexia but rather one endophenotype or risk factor., (Copyright © 2011. Published by Elsevier SAS.)