Inter-rater reliability and acceptance of the structured diagnostic interview for regulatory problems in infancy

Background: Regulatory problems such as excessive crying, sleeping–and feeding difficulties in infancy are some of the earliest precursors of later mental health difficulties emerging throughout the lifespan. In the present study, the inter-rater reliability and acceptance of a structured computer-assisted diagnostic interview for regulatory problems (Baby-DIPS) was investigated. Methods: Using a community sample, 132 mothers of infants aged between 3 and 18 months (mean age = 10 months) were interviewed with the Baby-DIPS regarding current and former (combined = lifetime) regulatory problems. Severity of the symptoms was also rated. The interviews were conducted face-to-face at a psychology department at the university (51.5 %), the mother’s home (23.5 %), or via telephone (25.0 %). Inter-rater reliability was assessed with Cohen’s kappa (k). A sample of 48 mothers and their interviewers filled in acceptance questionnaires after the interview. Results: Good to excellent inter-rater reliability on the levels of current and lifetime regulatory problems (k = 0.77–0.98) were found. High inter-rater agreement was also found for ratings of severity (ICC = 0.86–0.97). Participants and interviewers’ overall acceptance ratings of the computer-assisted interview were favourable. Acceptance scores did not differ between interviews that revealed one or more clinically relevant regulatory problem(s) compared to those that revealed no regulatory problems. Conclusions: The Baby-DIPS was found to be a reliable instrument for the assessment of current and lifetime problems in crying and sleeping behaviours. The computer-assisted version of the Baby-DIPS was well accepted by interviewers and mothers. The Baby-DIPS appears to be well-suited for research and clinical use to identify infant regulatory problems

Sequence-Specific Features of Short Double-Strand, Blunt-End RNAs Have RIG-I- and Type 1 Interferon-Dependent or -Independent Anti-Viral Effects

Pathogen-associated molecular patterns, including cytoplasmic DNA and double-strand (ds)RNA trigger the induction of interferon (IFN) and antiviral states protecting cells and organisms from pathogens. Here we discovered that the transfection of human airway cell lines or non-transformed fibroblasts with 24mer dsRNA mimicking the cellular micro-RNA (miR)29b-1* gives strong anti-viral effects against human adenovirus type 5 (AdV-C5), influenza A virus X31 (H3N2), and SARS-CoV-2. These anti-viral effects required blunt-end complementary RNA strands and were not elicited by corresponding single-strand RNAs. dsRNA miR-29b-1* but not randomized miR-29b-1* mimics induced IFN-stimulated gene expression, and downregulated cell adhesion and cell cycle genes, as indicated by transcriptomics and IFN-I responsive Mx1-promoter activity assays. The inhibition of AdV-C5 infection with miR-29b-1* mimic depended on the IFN-alpha receptor 2 (IFNAR2) and the RNA-helicase retinoic acid-inducible gene I (RIG-I) but not cytoplasmic RNA sensors MDA5 and ZNFX1 or MyD88/TRIF adaptors. The antiviral effects of miR29b-1* were independent of a central AUAU-motif inducing dsRNA bending, as mimics with disrupted AUAU-motif were anti-viral in normal but not RIG-I knock-out (KO) or IFNAR2-KO cells. The screening of a library of scrambled short dsRNA sequences identified also anti-viral mimics functioning independently of RIG-I and IFNAR2, thus exemplifying the diverse anti-viral mechanisms of short blunt-end dsRNAsThe work was supported by the Swiss National Science Foundation (31003A_179256/1 to UFG, and 320030_205097 to JPS), the Swiss National Science Foundation SystemsX RTD InfectX (51RT 0_126008 to UFG and CvM), and the University Research Priority Program of the University of Zurich (URPP) ITINERARE – Innovative Therapies in Rare Diseases to JPS.Peer reviewe

Dissection of genetic associations with language-related traits in population-based cohorts

Recent advances in the field of language-related disorders have led to the identification of candidate genes for specific language impairment (SLI) and dyslexia. Replication studies have been conducted in independent samples including population-based cohorts, which can be characterised for a large number of relevant cognitive measures. The availability of a wide range of phenotypes allows us to not only identify the most suitable traits for replication of genetic association but also to refine the associated cognitive trait. In addition, it is possible to test for pleiotropic effects across multiple phenotypes which could explain the extensive comorbidity observed across SLI, dyslexia and other neurodevelopmental disorders. The availability of genome-wide genotype data for such cohorts will facilitate this kind of analysis but important issues, such as multiple test corrections, have to be taken into account considering that small effect sizes are expected to underlie such associations

Identification of Candidate Genes for Dyslexia Susceptibility on Chromosome 18

Background: Six independent studies have identified linkage to chromosome 18 for developmental dyslexia or general reading ability. Until now, no candidate genes have been identified to explain this linkage. Here, we set out to identify the gene(s) conferring susceptibility by a two stage strategy of linkage and association analysis. Methodology/Principal Findings: Linkage analysis: 264 UK families and 155 US families each containing at least one child diagnosed with dyslexia were genotyped with a dense set of microsatellite markers on chromosome 18. Association analysis: Using a discovery sample of 187 UK families, nearly 3000 SNPs were genotyped across the chromosome 18 dyslexia susceptibility candidate region. Following association analysis, the top ranking SNPs were then genotyped in the remaining samples. The linkage analysis revealed a broad signal that spans approximately 40 Mb from 18p11.2 to 18q12.2. Following the association analysis and subsequent replication attempts, we observed consistent association with the same SNPs in three genes; melanocortin 5 receptor (MC5R), dymeclin (DYM) and neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L). Conclusions: Along with already published biological evidence, MC5R, DYM and NEDD4L make attractive candidates for dyslexia susceptibility genes. However, further replication and functional studies are still required.Publisher PDFPeer reviewe

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Associations between problems with crying, sleeping and/or feeding in infancy and long-term behavioural outcomes in childhood : a meta-analysis

Background Excessive crying, sleeping or feeding problems are found in approximately 20% of infants and may predict behavioural problems in childhood. Methods A quantitative meta-analysis of 22 longitudinal studies from 1987 to 2006 that statistically tested the association between infant regulatory problems and childhood internalising, externalising and attention-deficit/hyperactivity disorder (ADHD) problems was carried out; 1935 children with regulatory problems were tested. Cohen's d was used to express the association between regulatory problems and behavioural problems. Heterogeneity of the effect sizes was assessed using the I 2 statistic and meta-analysis of variance and meta-regressions were conducted to assess the influence of moderators. Rosenthal's classic fail-safe N and correlation of sample sizes to effect sizes were used to assess publication bias. Results The weighted mean effect size for the main regulatory problems-behavioural problems association was 0.41 (95% CI 0.28 to 0.54), indicating that children with previous regulatory problems have more behavioural problems than controls. Externalising and ADHD problems were the strongest outcome of any regulatory problem, indicated by the highest fail-safe N and lowest correlation of sample size to effect size. Meta-analyses of variance revealed no significant moderating influences of regulatory problem comorbidity (I(2) = 44.0, p > 0.05), type (I(2) = 41.8, p > 0.05) or duration (I(2) = 44.0, p > 0.05). However, cumulative problems and clinical referral increased the risk of behavioural problems. Conclusions The meta-analyses suggest that children with previous regulatory problems have more behavioural problems than controls, particularly in multi-problem families. Further studies are required to assess the behavioural outcomes of previously sleep, feeding or multiply disturbed children

Inter-rater reliability and acceptance of the structured diagnostic interview for regulatory problems in infancy

$\textbf {Background:}$ Regulatory problems such as excessive crying, sleeping–and feeding difficulties in infancy are some of the earliest precursors of later mental health difficulties emerging throughout the lifespan. In the present study, the inter rater reliability and acceptance of a structured computer assisted diagnostic interview for regulatory problems (Baby DIPS) was investigated. $\textbf {Methods:}$ Using a community sample, 132 mothers of infants aged between 3 and 18 months (mean age = 10 months) were interviewed with the Baby DIPS regarding current and former (combined = lifetime) regulatory problems. Severity of the symptoms was also rated. The interviews were conducted face to face at a psychology department at the university (51.5 %), the mother’s home (23.5 %), or via telephone (25.0 %). Inter rater reliability was assessed with Cohen’s kappa $\textit {(k)}$. A sample of 48 mothers and their interviewers filled in acceptance questionnaires after the interview. $\textbf {Results:}$ Good to excellent inter rater reliability on the levels of current and lifetime regulatory problems ($\it k$ = 0.77–0.98) were found. High inter rater agreement was also found for ratings of severity ($\it ICC$ = 0.86–0.97). Participants and interviewers’ overall acceptance ratings of the computer assisted interview were favourable. Acceptance scores did not differ between interviews that revealed one or more clinically relevant regulatory problem(s) compared to those that revealed no regulatory problems. $\textbf {Conclusions:}$ The Baby DIPS was found to be a reliable instrument for the assessment of current and lifetime problems in crying and sleeping behaviours. The computer assisted version of the Baby DIPS was well accepted by interviewers and mothers. The Baby DIPS appears to be well suited for research and clinical use to identify infant regulatory problems