The relations between maternal language input and language development for children with Williams syndrome.

For typically developing (TD) children, maternal language input (MLI) is an important contributor to early language development. Until now, possible relations between MLI and language development for children with Williams syndrome (WS), a genetic neurodevelopmental disorder associated with language delay and intellectual disability, have not been addressed. The aim of the present study was two-fold: to examine concurrent relations between MLI and child language abilities at 24 months and to determine if individual differences in MLI and children’s lexical and cognitive abilities at 24 months make significant unique contributions to the variance in child language abilities at 48 months for children with WS. Participants included 34 mother-child dyads. Lexical diversity (number of different words; NDW) and grammatical complexity (mean length of utterance in morphemes; MLUm) measures of MLI were assessed during a 30-minute naturalistic play session at 24 months of age. For the child, standardized assessments of language and cognitive ability, as well as lexical (NDW) and grammatical (MLUm) ability measures from the play session were collected at 24 and 48 months of age. Mothers also completed a parent-report measure of child lexical and grammatical abilities at both ages. Concurrent relations between MLI and child measures of language and cognitive development were significant for maternal NDW but not for maternal MLUm. Regression analyses indicated that maternal NDW contributed significant unique variance to child receptive language at 48 months, even after taking into account child 24-month expressive vocabulary and 24-month nonverbal reasoning ability. Maternal MLUm accounted for significant unique variance in child receptive language and child MLUm at 48 months, even after accounting for the contributions of child 24-month expressive vocabulary and nonverbal reasoning ability. Implications of these findings are discussed

Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin–actin association or tropomyosin head-to-tail binding

Regional socioeconomic indicators and ethnicity as predictors of regional infant mortality rate in Slovakia

OBJECTIVE: Exploring the associations of regional differences in infant mortality with selected socioeconomic indicators and ethnicity could offer important clues for designing public health policy measures. METHODS: Data included perinatal and infant mortality in the 79 districts of the Slovak population in 2004. Linear regression was used to analyse the contribution of education, unemployment, income and proportion of Roma population on regional differences in perinatal and infant mortality rates. RESULTS: All the explored socioeconomic indicators and ethnicity individually contributed significantly to both perinatal and infant mortality, with the exception of income. In the model exploring the influence of all these variables together on perinatal and infant mortality, only the effect of the proportion of Roma population remained significant. This model explained 34.9% of the variance for perinatal and 36.4% of the variance for infant mortality. CONCLUSIONS: Living in Roma settlements indicates an accumulation of socioeconomic disadvantage. Health literacy, health-related behaviour and many other factors might contribute to the explanation of the differences in infant mortality, and a better understanding of these processes might help us to design tailored interventions

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Characteristics of innovation policy mixes in multi-level government system: the case of the Baltic Sea Region countries

Elektroniskā versija nesatur pielikumusPromocijas darbā pētīts, kā notiek inovācijas rīcībpolitikas paralēla plānošana un ieviešana dažādos pārvaldes līmeņos – vietējā, nacionālā un pārnacionālā. Analizētas divas gadījumu grupas – Baltijas valstis un Somija, Zviedrija un Dānija – kas atšķiras pēc inovācijas rīcībpolitikas īstenošanā aktīvi iesaistīto pārvaldes līmeņu skaita. Darba teorētiskais ietvars ir daudzlīmeņu pārvaldības un rīcībpolitiku kombināciju koncepti, kas izmantoti kvalitatīvo datu analīzes kategoriju izstrādei. Gadījumi analizēti un salīdzināti, izmantojot politikas plānošanas dokumentus un veicot padziļinātās intervijas ar rīcībpolitikas veidotājiem katrā pārvaldes līmenī. Hipotēze, kurā tika pieņemts, ka daudzlīmeņu inovācijas rīcībpolitikas kombinācijas raksturo nesaskaņotība, netika pierādīta, taču starp pārvaldes līmeņiem nevar novērot arī pozitīvu sinerģiju.Dissertation explores how innovation policy is planned and implemented at different levels of government - local, national and transnational. Two groups of cases are analysed - the Baltic States and Denmark, Sweden and Finland. The groups of cases differ according to the number of government levels involved in the innovation policy making. The theoretical frameworks of the thesis are the concepts of policy mix and multi-level governance. Both are used to develop the categories for qualitative data analysis. The cases are analysed and compared using the policy planning documents and conducting in-depth interviews with policy makers at each level of government. The hypothesis, which assumed that multi-level innovation policy mixes are incoherent, was not proved, however, interaction between government levels was not identified either

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins