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Grip strength (GS) is a proxy measure for muscular strength and a predictor for bone fracture risk among other diseases. Previous genome-wide association studies (GWASs) have been conducted in large cohorts of adults focusing on scores collected for the dominant hand, therefore increasing the likelihood of confounding effects by environmental factors. Here, we perform the first GWAS meta-analyses on maximal GS with the dominant (GSD) and non-dominant (GSND) hand in two cohorts of children (ALSPAC, N = 5450; age range = 10.65-13.61; Raine Study, N = 1162, age range: 9.42-12.38 years). We identified a novel significant association for GSND (rs9546244, LINC02465, p = 3.43e-08) and replicated associations previously reported in adults including with a HOXB3 gene marker that shows an expression quantitative trait locus (eQTL) effect. Despite a much smaller sample (~3%) compared with the UK Biobank we replicated correlation analyses previously reported in this much larger adult cohort, such as a negative correlation with coronary artery disease. Although the results from the polygenic risk score (PRS) analyses did not survive multiple testing correction, we observed nominally significant associations between GS and risk of overall fracture, as previously reported, as well ADHD which will require further investigations. Finally, we observed a higher SNP-heritability (24%-41%) compared with previous studies (4%-24%) in adults. Overall, our results suggest that cohorts of children might be better suited for genetic studies of grip strength, possibly due to the shorter exposure to confounding environmental factors compared with adults., (© 2024 The Author(s). Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

The frequency of left-handedness in humans is ~10% worldwide and slightly higher in males than females. Twin and family studies estimate the heritability of human handedness at around 25%. The low but substantial frequency of left-handedness has been suggested to imply negative frequency-dependent selection, e.g. owing to a 'surprise' advantage of left-handers in combat against opponents more used to fighting right-handers. Because such game-theoretic hypotheses involve social interaction, here we perform an analysis of the evolution of handedness based on kin-selection, which is understood to play a major role in the evolution of social behaviour generally. We show that: (1) relatedness modulates the balance of right-handedness vs. left-handedness, according to whether left-handedness is marginally selfish vs. marginally altruistic; (2) sex differences in relatedness to social partners may drive sex differences in handedness; (3) differential relatedness of parents and offspring may generate parent-offspring conflict and sexual conflict leading to the evolution of maternal and paternal genetic effects in relation to handedness; and (4) differential relatedness of maternal-origin vs. paternal-origin genes may generate intragenomic conflict leading to the evolution of parent-of-origin-specific gene effects - such as 'genomic imprinting' - and associated maladaptation., Competing Interests: None., (© The Author(s) 2024.)

Dyslexia and developmental language disorders are important learning difficulties. However, their genetic basis remains poorly understood, and most genetic studies were performed on Europeans. There is a lack of genome-wide association studies (GWAS) on literacy phenotypes of Chinese as a native language and English as a second language (ESL) in a Chinese population. In this study, we conducted GWAS on 34 reading/language-related phenotypes in Hong Kong Chinese bilingual children (including both twins and singletons; total N = 1046). We performed association tests at the single-variant, gene, and pathway levels. In addition, we tested genetic overlap of these phenotypes with other neuropsychiatric disorders, as well as cognitive performance (CP) and educational attainment (EA) using polygenic risk score (PRS) analysis. Totally 5 independent loci (LD-clumped at r 2  = 0.01; MAF > 0.05) reached genome-wide significance (p < 5e-08; filtered by imputation quality metric Rsq>0.3 and having at least 2 correlated SNPs (r 2  > 0.5) with p < 1e-3). The loci were associated with a range of language/literacy traits such as Chinese vocabulary, character and word reading, and rapid digit naming, as well as English lexical decision. Several SNPs from these loci mapped to genes that were reported to be associated with EA and other neuropsychiatric phenotypes, such as MANEA and PLXNC1. In PRS analysis, EA and CP showed the most consistent and significant polygenic overlap with a variety of language traits, especially English literacy skills. To summarize, this study revealed the genetic basis of Chinese and English abilities in a group of Chinese bilingual children. Further studies are warranted to replicate the findings., (© 2024. The Author(s).)

A longstanding cerebral lateralization hypothesis predicts that disrupted development of typical leftward structural asymmetry of auditory cortex explains why children have problems learning to read. Small sample sizes and small effects, potential sex-specific effects, and associations that are limited to specific dimensions of language are thought to have contributed inconsistent results. The large ABCD study dataset (baseline visit: N = 11,859) was used to test the hypothesis of significant associations between surface area asymmetry of auditory cortex and receptive vocabulary performance across boys and girls, as well as an oral word reading effect that was specific to boys. The results provide modest support (Cohen's d effect sizes ≤ 0.10) for the cerebral lateralization hypothesis.

Since almost a hundred years, psychologists have investigated the link between hand preference and dyslexia. We present a meta-analysis to determine whether there is indeed an increase in atypical hand preference in dyslexia. We included studies used in two previous meta-analyses (Bishop, 1990; Eglinton & Annett, 1994) as well as studies identified through PubMed MEDLINE, PsycInfo, Google Scholar, and Web of Science up to August 2022. K = 68 studies (n = 4660 individuals with dyslexia; n = 40845 controls) were entered into three random effects meta-analyses using the odds ratio as the effect size (non-right-handers; left-handers; mixed-handers vs. total). Evidence of elevated levels of atypical hand preference in dyslexia emerged that were especially pronounced for mixed-hand preference (OR = 1.57), although this category was underdefined. Differences in (direction or degree) of hand skill or degree of hand preference could not be assessed as no pertinent studies were located. Our findings allow for robust conclusions only for a relationship of mixed-hand preference with dyslexia., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

A recent genome-wide association study on dyslexia in 51,800 affected European adults and 1,087,070 controls detected 42 genome-wide significant single nucleotide variants (SNPs). The association between rs2624839 in SEMA3F and reading fluency was replicated in a Chinese cohort. This study explores the genetic overlap between Chinese and English word reading, vocabulary knowledge and spelling, and aims at replicating the association in a unique cohort of bilingual (Chinese-English) Hong Kong Chinese twins. Our result showed an almost complete genetic overlap in vocabulary knowledge (r 2  = 0.995), and some genetic overlaps in word reading and spelling (r 2  = 0.846, 0.687) across the languages. To investigate the region near rs2624839, we tested proxy SNPs (rs1005678, rs12632110 and rs12494414) at the population level (n = 305-308) and the within-twin level (n = 342-344 [171-172 twin pairs]). All the three SNPs showed significant associations with quantitative Chinese and English vocabulary knowledge (p < 0.05). The strongest association after multiple testing correction was between rs12494414 and English vocabulary knowledge at the within-twin level (p = 0.004). There was a trend of associations with word reading and spelling in English but not in Chinese. Our result suggested that the region near rs2624839 is one of the common genetic factors across English and Chinese vocabulary knowledge and unique factors of English word reading and English spelling in bilingual Chinese twins. A larger sample size is required to validate our findings. Further studies on the relationship between variable expression of SEMA3F, which is important to neurodevelopment, and language and literacy are encouraged., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Visual acuity significantly contributes to quality of life. Deficits in childhood are associated with reading difficulties, which can have detrimental effects on education outcomes. In adults, it has been observed that vision defects such as myopia are associated with higher educational attainment (EA). Understanding genetic factors contributing to visual acuity could help to dissect its links with cognitive skills, neurodevelopmental conditions, and education. We examined associations between distance visual acuity, cognitive measures including school grades, and neurodevelopmental conditions in a longitudinal cohort of British children (ALSPAC, n = 6807, M age = 11.8). We performed a genome-wide association study (GWAS, n = 5571) on visual acuity and tested for genetic associations with relevant phenotypes using polygenic scores (PGS) and genetic correlation analyses. Visual acuity was associated with better cognitive performance and school grades, and reduced in individuals with reading difficulties compared to controls. GWAS revealed genetic associations at the NPLOC4 locus and highlighted other genes involved in sensory function. In line with positive genetic correlations between visual acuity and cognitive measures, EA PGS were positively associated with visual acuity, while there was a less robust negative association with myopia PGS. In conclusion, increased visual acuity is associated with a range of positive outcomes, including better school grades. Our results suggest an association between a higher EA PGS and slightly increased visual acuity in childhood. This could indicate gene-environment correlation, in which environmental exposures linked to higher EA might have detrimental effects on vision offsetting the initial positive effect., (© 2023. The Author(s).)

Handedness has been studied for association with language-related disorders because of its link with language hemispheric dominance. No clear pattern has emerged, possibly because of small samples, publication bias, and heterogeneous criteria across studies. Non-right-handedness (NRH) frequency was assessed in N = 2503 cases with reading and/or language impairment and N = 4316 sex-matched controls identified from 10 distinct cohorts (age range 6-19 years old; European ethnicity) using a priori set criteria. A meta-analysis (N cases  = 1994) showed elevated NRH % in individuals with language/reading impairment compared with controls (OR = 1.21, CI = 1.06-1.39, p = .01). The association between reading/language impairments and NRH could result from shared pathways underlying brain lateralization, handedness, and cognitive functions., (© 2023 The Authors. Child Development published by Wiley Periodicals LLC on behalf of Society for Research in Child Development.)

Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia., (© 2022. The Author(s).)

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.

Left-right asymmetries in the nervous system (lateralisation) influence a broad range of behaviours, from social responses to navigation and language. The role and pathways of endogenous and environmental mechanisms in the ontogeny of lateralisation remains to be established. The domestic chick is a model of both endogenous and experience-induced lateralisation driven by light exposure. Following the endogenous rightward rotation of the embryo, the asymmetrical position in the egg results in a greater exposure of the right eye to environmental light. To identify the genetic pathways activated by asymmetric light stimulation, and their time course, we exposed embryos to different light regimes: darkness, 6 h of light and 24 h of light. We used RNA-seq to compare gene expression in the right and left retinas and telencephalon. We detected differential gene expression in right vs left retina after 6 h of light exposure. This difference was absent in the darkness condition and had already disappeared by 24 h of light exposure, suggesting that light-induced activation is a self-terminating phenomenon. This transient effect of light exposure was associated with a downregulation of the sensitive-period mediator gene DIO2 (iodothyronine deiodinase 2) in the right retina. No differences between genes expressed in the right vs. left telencephalon were detected. Gene networks associated with lateralisation were connected to vascularisation, cell motility, and the extracellular matrix. Interestingly, we know that the extracellular matrix-including the differentially expressed PDGFRB gene-is involved in morphogenesis, sensitive periods, and in the endogenous chiral mechanism of primary cilia, that drives lateralisation. Our data show a similarity between endogenous and experience-driven lateralisation, identifying functional gene networks that affect lateralisation in a specific time window., (© 2022. The Author(s).)

The aim of our study was to evaluate the benefits of a low-pressure insufflation system (AirSeal) vs. a standard insufflation system in terms of anesthesiologists’ parameters and postoperative pain in patients undergoing laparoscopic surgery for early-stage endometrial cancer. This retrospective study involved five tertiary centers and included 152 patients with apparent early-stage disease who underwent laparoscopic surgical staging with either the low-pressure AirSeal system (8−10 mmHg, n = 84) or standard laparoscopic insufflation (10−12 mmHg, n = 68). All the intraoperative anesthesia variables evaluated (systolic blood pressure, end-tidal CO2, peak airway pressure) were significantly lower in the AirSeal group. We recorded a statistically significant difference between the two groups in the median NRS scores for global pain recorded at 4, 8, and 24 h, and for overall shoulder pain after surgery. Significantly more women in the AirSeal group were also discharged on day one compared to the standard group. All such results were confirmed when analyzing the subgroup of women with a BMI >30 kg/m2. In conclusion, according to our preliminary study, low-pressure laparoscopy represents a valid alternative to standard laparoscopy and could facilitate the development of outpatient surgery.

Handedness is the most commonly investigated lateralised phenotype and is usually measured as a binary left/right category. Its links with psychiatric and neurodevelopmental disorders prompted studies aimed at understanding the underlying genetics, while other measures and side preferences have been less studied. We investigated the heritability of hand, as well as foot, and eye preference by assessing parental effects (n ≤ 5028 family trios) and SNP-based heritability (SNP-h 2 , n ≤ 5931 children) in the Avon Longitudinal Study of Parents and Children (ALSPAC). An independent twin cohort from Hong Kong (n = 358) was used to replicate results from structural equation modelling (SEM). Parental left-side preference increased the chance of an individual to be left-sided for the same trait, with stronger maternal than paternal effects for footedness. By regressing out the effects of sex, age, and ancestry, we transformed laterality categories into quantitative measures. The SNP-h 2 for quantitative handedness and footedness was 0.21 and 0.23, respectively, which is higher than the SNP-h 2 reported in larger genetic studies using binary handedness measures. The heritability of the quantitative measure of handedness increased (0.45) compared to a binary measure for writing hand (0.27) in the Hong Kong twins. Genomic and behavioural SEM identified a shared genetic factor contributing to handedness, footedness, and eyedness, but no independent effects on individual phenotypes. Our analysis demonstrates how quantitative multidimensional laterality phenotypes are better suited to capture the underlying genetics than binary traits., (© 2022. The Author(s).)

Background: In the general population, 10.6% of people favor their left hand over the right for motor tasks. Previous research suggests higher prevalence of atypical (left-, mixed-, or non-right-) handedness in (i) twins compared to singletons, and in (ii) monozygotic compared to dizygotic twins. Moreover, (iii) studies have shown a higher rate of handedness concordance in monozygotic compared to dizygotic twins, in line with genetic factors playing a role for handedness., Methods: By means of a systematic review, we identified 59 studies from previous literature and performed three sets of random effects meta-analyses on (i) twin-to-singleton Odds Ratios (21 studies, n = 189,422 individuals) and (ii) monozygotic-to-dizygotic twin Odds Ratios (48 studies, n = 63,295 individuals), both times for prevalence of left-, mixed-, and non-right-handedness. For monozygotic and dizygotic twin pairs we compared (iii) handedness concordance Odds Ratios (44 studies, n = 36,217 twin pairs). We also tested for potential effects of moderating variables, such as sex, age, the method used to assess handedness, and the twins' zygosity., Results: We found (i) evidence for higher prevalence of left- (Odds Ratio = 1.40, 95% Confidence Interval = [1.26, 1.57]) and non-right- (Odds Ratio = 1.36, 95% Confidence Interval = [1.22, 1.52]), but not mixed-handedness (Odds Ratio = 1.08, 95% Confidence Interval = [0.52, 2.27]) among twins compared to singletons. We further showed a decrease in Odds Ratios in more recent studies (post-1975: Odds Ratio = 1.30, 95% Confidence Interval = [1.17, 1.45]) compared to earlier studies (pre-1975: Odds Ratio = 1.90, 95% Confidence Interval = [1.59-2.27]). While there was (ii) no difference between monozygotic and dizygotic twins regarding prevalence of left- (Odds Ratio = 0.98, 95% Confidence Interval = [0.89, 1.07]), mixed- (Odds Ratio = 0.96, 95% Confidence Interval = [0.46, 1.99]), or non-right-handedness (Odds Ratio = 1.01, 95% Confidence Interval = [0.91, 1.12]), we found that (iii) handedness concordance was elevated among monozygotic compared to dizygotic twin pairs (Odds Ratio = 1.11, 95% Confidence Interval = [1.06, 1.18]). By means of moderator analyses, we did not find evidence for effects of potentially confounding variables., Conclusion: We provide the largest and most comprehensive meta-analysis on handedness in twins. Although a raw, unadjusted analysis found a higher prevalence of left- and non-right-, but not mixed-handedness among twins compared to singletons, left-handedness was substantially more prevalent in earlier than in more recent studies. The single large, recent study which included birth weight, Apgar score and gestational age as covariates found no twin-singleton difference in handedness rate, but these covariates could not be included in the present meta-analysis. Together, the secular shift and the influence of covariates probably make it unsafe to conclude that twinning has a genuine relationship to handedness., (© 2022. The Author(s).)

Following its association with dyslexia in multiple genetic studies, the KIAA0319 gene has been extensively investigated in different animal models but its function in neurodevelopment remains poorly understood. We developed the first human cellular knockout model for KIAA0319 in RPE1 retinal pigment epithelia cells via CRISPR-Cas9n to investigate its role in processes suggested but not confirmed in previous studies, including cilia formation and cell migration. We observed in the KIAA0319 knockout increased cilia length and accelerated cell migration. Using Elastic Resonator Interference Stress Microscopy (ERISM), we detected an increase in cellular force for the knockout cells that was restored by a rescue experiment. Combining ERISM and immunostaining we show that RPE1 cells exert highly dynamic, piconewton vertical pushing forces through actin-rich protrusions that are surrounded by vinculin-rich pulling sites. This protein arrangement and force pattern has previously been associated to podosomes in other cells. KIAA0319 depletion reduces the fraction of cells forming these actin-rich protrusions. Our results suggest an involvement of KIAA0319 in cilia biology and cell-substrate force regulation., (© 2022. The Author(s).)

Dyslexia, a specific reading disability, is a common (up to 10% of children) and highly heritable (~70%) neurodevelopmental disorder. Behavioral and molecular genetic approaches are aimed towards dissecting its significant genetic component. In the proposed review, we will summarize advances in twin and molecular genetic research from the past 20 years. First, we will briefly outline the clinical and educational presentation and epidemiology of dyslexia. Next, we will summarize results from twin studies, followed by molecular genetic research (e.g., genome-wide association studies (GWASs)). In particular, we will highlight converging key insights from genetic research. (1) Dyslexia is a highly polygenic neurodevelopmental disorder with a complex genetic architecture. (2) Dyslexia categories share a large proportion of genetics with continuously distributed measures of reading skills, with shared genetic risks also seen across development. (3) Dyslexia genetic risks are shared with those implicated in many other neurodevelopmental disorders (e.g., developmental language disorder and dyscalculia). Finally, we will discuss the implications and future directions. As the diversity of genetic studies continues to increase through international collaborate efforts, we will highlight the challenges in advances of genetics discoveries in this field.

Objective: The aim of this study was to assess incidence, causes and consequences of equipment failures in a high volume, advanced endoscopic surgery department., Methods: This is a prospectical observational single centre study between April and July of 2019 in the Gynecological surgery department of the Estaing University Hospital of Clermont-Ferrand, France. During the study period, 171 laparoscopies were observed. Data were collected real time by three supernumerary observers., Results: In total, 66 (38.6%) laparoscopies were complicated by equipment failures. The bipolar cable and forceps accounted for 31% of the total amount of malfunctions in laparoscopy. Causes of malfunctions were in 45% due to the instrument per se and in 43% due to the incorrect combination of elements. Less commonly, the equipment was not available or a mismatched was reported. The total length of the surgery increased by 1.35% due to the malfunctions. Human error was identified in 50% of cases. No morbility, neither mortality was reported in this series; however we observed 34 malfunctions that could have led to serious consequences for the patients and 3 incidents induced a real consequence on the operation workflow., Conclusions: Equipment failure is a common event in endoscopy. On the opposite, time wasted for the malfunctions is low in laparoscopy, as it only accounts for 1.35% of the overall surgical time. Human decisions contributed to malfunctions in almost half of cases. This alarming finding may advise for intensification in training on instruments of the whole surgical team., (Copyright © 2020. Published by Elsevier Masson SAS.)

Increased rates of atypical handedness are observed in neurotypical individuals who are low-performing in mathematical tasks as well as in individuals with special educational needs, such as dyslexia. This is the first investigation of handedness in individuals with Mathematical Learning Difficulties (MLD). We report three new studies ( N  = 134; N  = 1,893; N  = 153) and two sets of meta-analyses (22 studies; N  = 3,667). No difference in atypical hand preference between MLD and Typically Achieving (TA) individuals was found when handedness was assessed with self-report questionnaires, but weak evidence of a difference was found when writing hand was the handedness criterion in Study 1 ( p  = .049). Similarly, when combining data meta-analytically, no hand preference differences were detected. We suggest that: (i) potential handedness effects require larger samples, (ii) direction of hand preference is not a sensitive enough measure of handedness in this context, or that (iii) increased rates of atypical hand preference are not associated with MLD. The latter scenario would suggest that handedness is specifically linked to language-related conditions rather than conditions related to cognitive abilities at large. Future studies need to consider hand skill and degree of hand preference in MLD.

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).)

An efficient auditory system contributes to cognitive and psychosocial development. A right ear advantage in hearing thresholds (HTs) has been described in adults and atypical patterns of left/right hearing threshold asymmetry (HTA) have been described for psychiatric and neurodevelopmental conditions. Previous genome-wide association studies (GWASs) on HT have mainly been conducted in elderly participants whose hearing is more likely to be affected by external environmental factors. Here, we investigated HT and HTA in a children population cohort (ALSPAC, n = 6,743). Better hearing was associated with better cognitive performance and higher socioeconomic status. At the group level, HTA suggested a left ear advantage (mean = -0.28 dB) that was mainly driven by females. SNP heritability for HT and HTA was 0.13 and 0.02, respectively (n = 4,989). We found a modest negative genetic correlation between HT and reading ability. GWAS for HT (n = 5,344) did not yield significant hits but polygenic risk scores for higher educational attainment (EA, ß = -1,564.72, p = .008) and schizophrenia (ß = -241.14, p = .004) were associated with lower HT, that is, better hearing. In summary, we report new data supporting associations between hearing measures and cognitive abilities at the behavioral level. Genetic analysis suggests shared biological pathways between cognitive and sensory systems and provides evidence for a positive outcome of genetic risk for schizophrenia., (© 2021 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

At least 5% of children present unexpected difficulties in expressing and understanding spoken language. This condition is highly heritable and often co-occurs with other neurodevelopmental disorders such as dyslexia and ADHD. Through an exome sequencing analysis, we identified a rare missense variant (chr16:84405221, GRCh38.p12) in the ATP2C2 gene. ATP2C2 was implicated in language disorders by linkage and association studies, and exactly the same variant was reported previously in a different exome sequencing study for language impairment (LI). We followed up this finding by genotyping the mutation in cohorts selected for LI and comorbid disorders. We found that the variant had a higher frequency in LI cases (1.8%, N = 360) compared with cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). Additionally, we observed that carriers of the rare variant identified from a general population cohort (N = 42, ALSPAC cohort) presented, as a group, lower scores on a range of reading and language-related measures compared to controls (N = 1825; minimum P = 0.002 for non-word reading). ATP2C2 encodes for an ATPase (SPCA2) that transports calcium and manganese ions into the Golgi lumen. Our functional characterization suggested that the rare variant influences the ATPase activity of SPCA2. Thus, our results further support the role of ATP2C2 locus in language-related phenotypes and pinpoint the possible effects of a specific rare variant at molecular level., (© The Author(s) 2021. Published by Oxford University Press.)

Human lateral preferences, such as handedness and footedness, have interested researchers for decades due to their pronounced asymmetries at the population level. While there are good estimates on the prevalence of handedness in the population, there is no large-scale estimation on the prevalence of footedness. Furthermore, the relationship between footedness and handedness still remains elusive. Here, we conducted meta-analyses with four different classification systems for footedness on 145,135 individuals across 164 studies including new data from the ALSPAC cohort. The study aimed to determine a reliable point estimate of footedness, to study the association between footedness and handedness, and to investigate moderating factors influencing footedness. We showed that the prevalence of atypical footedness ranges between 12.10% using the most conservative criterion of left-footedness to 23.7% including all left- and mixed-footers as a single non-right category. As many as 60.1% of left-handers were left-footed whereas only 3.2% of right-handers were left-footed. Males were 4.1% more often non-right-footed compared to females. Individuals with psychiatric and neurodevelopmental disorders exhibited a higher prevalence of non-right-footedness. Furthermore, the presence of mixed-footedness was higher in children compared to adults and left-footedness was increased in athletes compared to the general population. Finally, we showed that footedness is only marginally influenced by cultural and social factors, which play a crucial role in the determination of handedness. Overall, this study provides new and useful reference data for laterality research. Furthermore, the data suggest that footedness is a valuable phenotype for the study of lateral motor biases, its underlying genetics and neurodevelopment.

Background: Structured laparoscopic training courses are important in surgical education. Different programmes have been proposed, but there is currently no evidence available comparing the performance of specialists versus residents in Obstetrics and Gynaecology at these courses., Objective: To evaluate the impact of the laparoscopic component of Gynaecological Endoscopic Surgical Education and Assessment (GESEA) Training and Certification courses in two different populations., Materials and Methods: Prospective cohort study. Two groups were analysed - participants of the Residents' Courses and participants of the Annual Francophone GESEA Diploma Course. Both groups were evaluated using the GESEA Level 1 laparoscopic standardised exercises and carried out in the International Center of Endoscopic Surgery (CICE), Clermont Ferrand, France in 2019., Results: 57 French residents and 69 participants of the Annual GESEA Diploma were evaluated. The average age of participants in the Residents' Course was lower than those in the Annual Diploma Course (28.4±1.6 versus 35.2±8.0 years, p<0.001). Residents had higher previous experience in laparoscopic surgery (42% vs 36%, p< 0.001), in animal model surgery and in laparoscopic training box (67% vs 36% and 93% vs 67% respectively, p<0.001). Notable improvement was noted in both groups in the camera navigation exercise; first attempt 105±19 vs 117±9 seconds and final attempt 81±15 and 103±20 seconds respectively (p<0.001)., Conclusions: Both groups improved significantly in most of the tests evaluated. French residents had better results in all evaluations, except in one aspect of the suture exercise (maintaining optimal results in performing the knot). After excluding the residents who attended the Annual Diploma Course, all the differences between both groups were statistically more significant., Competing Interests: Declaration of interest: None, (Copyright © 2020 Facts, Views & Vision.)

Across time and place, right hand preference has been the norm, but what is the precise prevalence of left- and right-handedness? Frequency of left-handedness has shaped and underpinned different fields of research, from cognitive neuroscience to human evolution, but reliable distributional estimates are still lacking. While hundreds of empirical studies have assessed handedness, a large-scale, comprehensive review of the prevalence of handedness and the factors that moderate it, is currently missing. Here, we report 5 meta-analyses on hand preference for different manual tasks and show that left-handedness prevalence lies between 9.3% (using the most stringent criterion of left-handedness) to 18.1% (using the most lenient criterion of nonright-handedness), with the best overall estimate being 10.6% (10.4% when excluding studies assessing elite athletes' handedness). Handedness variability depends on (a) study characteristics, namely year of publication and ways to measure and classify handedness, and (b) participant characteristics, namely sex and ancestry. Our analysis identifies the role of moderators that require taking into account in future studies on handedness and hemispheric asymmetries. We argue that the same evolutionary mechanisms should apply across geographical regions to maintain the roughly 1:10 ratio, while cultural factors, such as pressure against left-hand use, moderate the magnitude of the prevalence of left-handedness. Although handedness appears as a straightforward trait, there is no universal agreement on how to assess it. Therefore, we urge researchers to fully report study and participant characteristics as well as the detailed procedure by which handedness was assessed and make raw data publicly available. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Importance: The active-during-pregnancy-cancer (ADPC) is a condition that complicates the 0.1% of pregnancies. Abortion, preterm delivery and cesarean section (CS) are common attitudes for these patients, because of scarcity of evidence-based studies. Not-active-during-pregnancy-cancer (NADPC) is an increasing medical problem. The fertility of young girls survived to neoplasia is significantly lower compared to general population and there are increased rates of low birth weight and preterm birth. Objective: To analyze the impact that the pregnancy-related neoplastic disease has on management of deliveries in the decade 2006-2015. Material and methods: In this observational study, we collected obstetric and oncological data about 205 patients bearing a history of cancer related to pregnancy between January 2006 and September 2016 from Sant'Anna Hospital database archive in Turin. The entire population was divided in 59 patients with ADPC and 146 patients with NADPC because it was cured before starting the gestation. Three ADPC and three NADPC patients who completed their pregnancy in the year 2016 were excluded from the 10 years 2006-2015 trends realization. All in situ and invasive cancers were considered. Results: In ADPC patients, we registered 3.4% miscarriage and 15.3% iatrogenic abortion. The type of delivery was vaginal (22%) and CS (59.3%). Induction of labor was 14.6%, elective CS was 68.8%: the indication for these procedures was 78.6% oncological. The average gestational age was 35.5 weeks. In NADPC patients, we registered 9.6% miscarriage and 8.2% iatrogenic abortion. The type of delivery was vaginal (43.2%) and CS (39%). Induction of labor was 11.7%, elective CS was 36.7%: the indication for these procedures was 77.5% obstetrical. The average gestational age was 38.3 weeks. Conclusions: Ten-year trends in ADPC and NADPC patients showed an increase of induced deliveries and a decrease in elective CS. We observed not significant reduction of gestational age and birth weight. A contemporary decrease of oncological indications for CS in the two populations was reported.

Background: Left-handedness prevalence has been consistently reported at around 10% with heritability estimates at around 25%. Higher left-handedness prevalence has been reported in males and in twins. Lower prevalence has been reported in Asia, but it remains unclear whether this is due to biological or cultural factors. Most studies are based on samples with European ethnicities and using the preferred hand for writing as key assessment. Here, we investigated handedness in a sample of Chinese school children in Hong Kong, including 426 singletons and 205 pairs of twins, using both the Edinburgh Handedness Inventory and Pegboard Task., Results: Based on a binary definition of writing hand, we found a higher prevalence of left-handedness (8%) than what was previously reported in Asian datasets. We found no evidence of increased left-handedness in twins, but our results were in line with previous findings showing that males have a higher tendency to be left-handed than females. Heritability was similar for both hand preference (21%) and laterality indexes (22%). However, these two handedness measures present only a moderate correlation (.42) and appear to be underpinned by different genetic factors., Conclusion: In summary, we report new reference data for an ethnic group usually underrepresented in the literature. Our heritability analysis supports the idea that different measures will capture different components of handedness and, as a consequence, datasets assessed with heterogeneous criteria are not easily combined or compared.

The most common way to assess handedness is based on the preferred hand for writing, leading to a binary (left or right) trait. Handedness can also be assessed as a continuous trait with laterality indexes, but these are not time- and cost-effective, and are not routinely collected. Rarely, different handedness measures are collected for the same individuals. Here, we assessed the relationship of preferred hand for writing with four laterality indexes, reported in previous literature, derived from measures of dexterity (pegboard task, marking squares and sorting matches) and strength (grip strength), available in a range of N = 6664-8069 children from the ALSPAC cohort. Although all indexes identified a higher proportion of individuals performing better with their right hand, they showed low correlation with each other (0.08-0.3). Left handers were less consistent compared to right handers in performing better with their dominant hand, but that varied across indexes, i.e. 13% of left handers performed better with their right hand on marking squares compared to 48% for sorting matches and grip strength. Analysis of sex effects on the laterality indexes showed that males and females tend to be, on all measures, more left- and right-lateralized, respectively. Males were also over-represented among the individuals performing equally with both hands suggesting they had a higher tendency to be weakly lateralized. This study shows that different handedness measures tap into different dimensions of laterality and cannot be used interchangeably. The trends observed across indexes for males and females suggest that sex effects should be taken into account in handedness and laterality studies., Competing Interests: The authors have no competing interests to declare., (© 2020 The Authors.)

Objective: Laparoscopic cystectomy for endometrioma has the advantages of a minimally invasive approach. The standardization and description of the technique are the main objectives of this video. We described the surgery in 10 steps, which could help to make this procedure easier and safer., Design: Step-by-step video demonstration of the technique., Setting: A French university tertiary care hospital., Intervention: Two standardized laparoscopic cystectomy were recorded to realize the video. The local institutional review board ruled that approval was not required because the video describes a technique and does not report a clinical case. This video presents a systematic approach to cystectomy for endometrioma clearly divided into 10 steps: (1) preoperative evaluation [1]; (2) diagnosis and exploration [2]; (3) adhesiolysis, mobilization of the ovary; (4) cyst rupture, exposition of the entry site; (5) identification of the cleavage plan; (6) endometrioma easy dissection; (7) endometrioma difficult dissection; (8) hemostasis, reconstruction of the ovary [3]; (9) exploration of the ovarian fossa; and (10) washing, extraction of the cyst [3,4]., Conclusion: Standardization of laparoscopic cystectomy for endometrioma could make this procedure easier and safer to perform. The 10 steps presented help to perform each part of the surgery in a logical sequence, making the procedure easier to realize. Moreover, the standardization of the surgical techniques may reduce the learning curve., (Copyright © 2019 AAGL. Published by Elsevier Inc. All rights reserved.)

Background: Minimally-invasive video-assisted parathyroidectomy (MIVAP) can be considered as the primary treatment of choice for single parathyroid adenoma. Often, this technique is performed in a day surgery setting and is associated with regional anaesthesia (RA). Many studies have already reported the feasibility and safety of MIVAP in day surgery. Here our focus has been on the patient's personal experience with these procedures through an assessment of their recovery at home., Methods: We conducted a prospective observational study in the University Hospital of Pisa Day Surgery Unit. Forty-eight patients were enrolled and divided by personal choice of anaesthesia technique: a regional anaesthesia group (RAg) and general anaesthesia group (GAg). Data were extracted from the medical records and three questionnaires: the first was self-compiled at discharge (Q1), while the second (Q2) and the third (Q3) were administered as telephone surveys., Results: None of the patients in RAg reported pain longer than 1 day after discharge, whereas 15% of patients in GAg reported pain relief the third day after discharge (P=0.0065). Discharge in RAg was within 3 hours in 12.5% of patients, within 4 hours in 78.1%, and within 5 hours in 9.4%. Discharge in GAg was within 5 hours in 53.8% and in more than 5 hours in 46.1% (P=0.0027)., Conclusions: Patients highly appreciated day-case parathyroidectomy. Furthermore, the association of RA with MIVAP leads to better results than those of general anaesthesia (GA) and MIVAP. Finally, we point out that it is fundamental that the physicians pay attention to what the patients consider important for them; that is, the personal meaning of the hospitalization., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Gland Surgery. All rights reserved.)

Study Objective: Laparoscopic cystectomy for ovarian teratomas has the advantages of a minimally invasive approach [1]. The standardization and description of the technique are the main objectives of this video (Video 1). We described the surgery in 10 steps [2], which could help make this procedure easier and safer., Design: A step-by-step video demonstration of the technique., Setting: A French university tertiary care hospital., Patients: Patients with ovarian teratomas with indication for laparoscopic cystectomy [3]. The local institutional review board ruled that approval was not required for this video article because the video describes a technique and does not report a clinical case., Interventions: Standardized laparoscopic cystectomies were recorded to realize the video., Measurements and Main Results: This video presents a systematic approach to cystectomy for teratoma clearly divided into 10 steps: (1) planning of the surgery, (2) ergonomy and materials, (3) exploration and cytology, (4) prevention of peritoneal spillage [4], (5) mobilization of the ovary, (6) incision of the ovary, (7) dissection, (8) hemostasis, (9) exteriorization of the cyst, and (10) washing and exploration., Conclusion: Standardization of laparoscopic cystectomy for ovarian teratoma could make this procedure easier and safer to perform. The 10 steps presented help to perform each part of the surgery in a logical sequence, making the procedure ergonomic and easier to adopt and learn. Moreover, the standardization of the surgical techniques could reduce the learning curve., (Copyright © 2019. Published by Elsevier Inc.)

Dyslexia is a common neurodevelopmental disorder caused by a significant genetic component. The KIAA0319 gene is one of the most robust dyslexia susceptibility factors but its function remains poorly understood. Initial RNA-interference studies in rats suggested a role in neuronal migration whereas subsequent work with double knock-out mouse models for both Kiaa0319 and its paralogue Kiaa0319-like reported effects in the auditory system but not in neuronal migration. To further understand the role of KIAA0319 during neurodevelopment, we carried out an expression study of its zebrafish orthologue at different embryonic stages. We used different approaches including RNAscope in situ hybridization combined with light-sheet microscopy. The results show particularly high expression during the first few hours of development. Later, expression becomes localized in well-defined structures. In addition to high expression in the brain, we report for the first time expression in the eyes and the notochord. Surprisingly, kiaa0319-like, which generally shows a similar expression pattern to kiaa0319, was not expressed in the notochord suggesting a distinct role for kiaa0319 in this structure. This observation was supported by the identification of notochord enhancers enriched upstream of the KIAA0319 transcription start site, in both zebrafish and humans. This study supports a developmental role for KIAA0319 in the brain as well as in other developing structures, particularly in the notochord which, is key for establishing body patterning in vertebrates., (© 2019 The Authors. The Journal of Comparative Neurology published by Wiley Periodicals, Inc.)

Loss-of-function mutations in the SPART gene cause Troyer syndrome, a recessive form of spastic paraplegia resulting in muscle weakness, short stature, and cognitive defects. SPART encodes for Spartin, a protein linked to endosomal trafficking and mitochondrial membrane potential maintenance. Here, we identified with whole exome sequencing (WES) a novel frameshift mutation in the SPART gene in 2 brothers presenting an uncharacterized developmental delay and short stature. Functional characterization in an SH-SY5Y cell model shows that this mutation is associated with increased neurite outgrowth. These cells also show a marked decrease in mitochondrial complex I (NADH dehydrogenase) activity, coupled to decreased ATP synthesis and defective mitochondrial membrane potential. The cells also presented an increase in reactive oxygen species, extracellular pyruvate, and NADH levels, consistent with impaired complex I activity. In concordance with a severe mitochondrial failure, Spartin loss also led to an altered intracellular Ca 2+ homeostasis that was restored after transient expression of wild-type Spartin. Our data provide for the first time a thorough assessment of Spartin loss effects, including impaired complex I activity coupled to increased extracellular pyruvate. In summary, through a WES study we assign a diagnosis of Troyer syndrome to otherwise undiagnosed patients, and by functional characterization we show that the novel mutation in SPART leads to a profound bioenergetic imbalance.-Diquigiovanni, C., Bergamini, C., Diaz, R., Liparulo, I., Bianco, F., Masin, L., Baldassarro, V. A., Rizzardi, N., Tranchina, A., Buscherini, F., Wischmeijer, A., Pippucci, T., Scarano, E., Cordelli, D. M., Fato, R., Seri, M., Paracchini, S., Bonora, E. A novel mutation in SPART gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism.

Humans spend large portions of their time and energy talking to one another, yet it remains unclear whether this activity is primarily selfish or altruistic. Here, it is shown how parent-of-origin specific gene expression-or "genomic imprinting"-may provide an answer to this question. First, it is shown why, regarding language, only altruistic or selfish scenarios are expected. Second, it is pointed out that an individual's maternal-origin and paternal-origin genes may have different evolutionary interests regarding investment into language, and that this intragenomic conflict may drive genomic imprinting which-as the direction of imprint depends upon whether investment into language is relatively selfish or altruistic-may be used to discriminate between these two possibilities. Third, predictions concerning the impact of various mutations and epimutations at imprinted loci on language pathologies are derived. In doing so, a framework is developed that highlights avenues for using intragenomic conflicts to investigate the evolutionary drivers of language., (© 2019 The Authors. BioEssays Published by WILEY Periodicals, Inc.)

Purpose: To compare the performance of the algorithms proposed by the Fetal Medicine Foundation in 2012 and BCNatal in 2013 in an Italian population., Methods: A multicentric prospective study was carried out which included pregnancies at 11-13 weeks' gestation from Jan 2014 through May 2017. Two previously published algorithms were used for the calculation of the "a priori" risk of preeclampsia (based on risk factors from medical history) in each individual., Results: In a study population of 11,632 cases, 67 (0.6%) developed early preeclampsia and 211 (1.8%) developed late preeclampsia. The detection rates (95% CI) for early and late preeclampsia were 58.2% (45.5-70.2) vs. 41.8% (29.6-54.5) (p value < 0.05) and 44.1% (37.3-51.1) vs. 38% (31.3-44.8) (p value < 0.05) for the Fetal Medicine Foundation and BCNatal, respectively (at a 10% false positive rate). The associated risk was 1:226 and 1:198 (p value ns) for early PE, and 1:17 and 1:24 (p value ns) for late PE for the Fetal Medicine Foundation and BCNatal, respectively., Conclusions: The Fetal Medicine Foundation screening for preeclampsia at 11-13 weeks' gestation scored the highest detection rate for both early and late PE. At a fixed 10% false positive rate, the estimated "a priori" risks of both the Fetal Medicine Foundation and the BCNatal algorithms in an Italian population were quite similar, and both were reliable and consistent.

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.

The capacity for language is one of the key features underlying the complexity of human cognition and its evolution. However, little is known about the neurobiological mechanisms that mediate normal or impaired linguistic ability. For developmental dyslexia, early postmortem studies conducted in the 1980s linked the disorder to subtle defects in the migration of neurons in the developing neocortex. These early studies were reinforced by human genetic analyses that identified dyslexia susceptibility genes and subsequent evidence of their involvement in neuronal migration. In this review, we examine recent experimental evidence that does not support the link between dyslexia and neuronal migration. We critically evaluate gene function studies conducted in rodent models and draw attention to the lack of robust evidence from histopathological and imaging studies in humans. Our review suggests that the neuronal migration hypothesis of dyslexia should be reconsidered, and the neurobiological basis of dyslexia should be approached with a fresh start., (© 2018 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: The aim of the study was to investigate whether the angle of progression (AoP), as measured by transperineal ultrasound, was predictive of both the time remaining in labor and vaginal delivery., Methods: This was a prospective observational cohort study involving 270 low-risk women with singleton pregnancies at term. The AoP, measured at the end of the first stage of labor, was used as a predictive variable of time remaining in labor and mode of delivery. The Kaplan Meier and Cox algorithms were used to evaluate the time elapsed between AoP measurement and delivery as a function of AoP. Instead, logistic regression was used to calculate the adjusted probability of vaginal delivery as a function of AoP., Results: Of the 270 women enrolled, 15 (5.6%) delivered by cesarean section and 33 (12.1%) by vacuum or forceps. The AoP, stratified by quartiles, was a significant predictor of the time remaining in labor, even after adjustment for possible confounders (Body Mass Index [BMI], oxytocin administration and parity). The mean±SD second stage of labor length for each AoP quartile was 134±25, 126±18, 96±33 and 58±23 minutes (P value<0.001, ANOVA). The mean±SD probability of a vaginal delivery expressed as a function of the AoP quartile (adjusted for BMI) was 51.5±0.16%, 81.5±0.10%, 97.0±0.16% and 99.3±0.004% at the AoP of the 1st, 2nd, 3rd and 4th quartiles, respectively, (P value<0.001 ANOVA)., Conclusions: The AoP was directly associated with the time remaining in labor and was predictive of a successful vaginal delivery; however, the impact on clinical practice seems low.

Background: The rate of cesarean delivery is currently increasing all over Europe. In Italy it reaches 38% of all child births. Therefore, it is important to identify the clinical and organizational variables that determine the appropriateness of elective cesarean delivery. With this aim we chose the technology of clinical audit, a process that promotes improvement in clinical practice through systematic review of clinical care in relation with explicit standards derived from scientific literature., Methods: This is a prospective audit: in the period March 2014-July 2014 we analyzed the medical records of 150 women who underwent elective cesarean delivery at Gynecological and Obstetrical University Hospital Sant'Anna, Turin. We collected data related to five quality criteria derived from scientific literature. Each criterion was stratified by indicators and matched with respective standards of adequate care. Criteria and indicators are: 1) cesarean section (CS) rate in twin pregnancies with both cephalic fetal presentation (stratified by dichorionic diamniotic and monochorionic diamniotic); 2) CS rates in preterm births (stratified by gestational age ≤32, ≤34 and ≤37 week); 3) CS rates on maternal request due to tokophobia in patients who received a psychological support during pregnancy; 4) repeated CS rates; 5) multidisciplinary evaluation of the indication to CS for non-obstetric reasons (orthopedic, ophthalmologic, psychiatric and neurological). The rate of CSs found in each criterion was compared with the respective standard in literature. The value obtained for each indicator was tested for statistical significance (CI 95%). We considered performing indicators whose final rate was found to be better or equal to the reference standard., Results: The majority of the indicators result to be performant. CS rate for previous CS was 84% (73/86), far more frequent than the standard of optimal care fixed at ≤30% (P<0.05). Repeated CSs were analyzed in steps IV and V of audit because of the high gap between observed and adequate scores, the significant potential of improvement and the high incidence of the event, as they account for the 20% of average cesarean deliveries in our unit in the period of the study. Thus, we implemented a plan of improvement that consisted on introduction in clinical practice of the cervical ripening balloon for women who desire a trial of labor after CS (TOLAC), congress sessions and training to clinicians, information and counselling to pregnant woman with a previous cesarean. The impact of the implemented measures of correction applied for two years was evaluated with a re-audit on 40 patients, from May to April 2016. The cesarean birth after cesarean (CBAC) rate observed after the re-audit was 62% (32/50), significantly lower compared to the previous 80% P<0.01. Thus, the established plan of improvement induces a reduction in CBAC rate of 24%., Conclusions: Clinical audit is a powerful instrument that can improve standards of care. In our Unit, clinical audit on elective cesarean leads to the identification of an excess in repeated cesareans and a significant reduction of them. However, to realize an effective improvement we are planning furthers audits.

Dyslexia is a specific impairment in learning to read and has strong heritability. An intronic deletion within the DCDC2 gene, with ~8% frequency in European populations, is increasingly used as a marker for dyslexia in neuroimaging and behavioral studies. At a mechanistic level, this deletion has been proposed to influence sensory processing capacity, and in particular sensitivity to visual coherent motion. Our re-assessment of the literature, however, did not reveal strong support for a role of this specific deletion in dyslexia. We also analyzed data from five distinct cohorts, enriched for individuals with dyslexia, and did not identify any signal indicative of associations for the DCDC2 deletion with reading-related measures, including in a combined sample analysis (N=526). We believe we conducted the first replication analysis for a proposed deletion effect on visual motion perception and found no association (N=445 siblings). We also report that the DCDC2 deletion has a frequency of 37.6% in a cohort representative of the general population recruited in Hong Kong (N=220). This figure, together with a lack of association between the deletion and reading abilities in this cohort, indicates the low likelihood of a direct deletion effect on reading skills. Therefore, on the basis of multiple strands of evidence, we conclude that the DCDC2 deletion is not a strong risk factor for dyslexia. Our analyses and literature re-evaluation are important for interpreting current developments within multidisciplinary studies of dyslexia and, more generally, contribute to current discussions about the importance of reproducibility in science.

Background: Specific language impairment (SLI) is a common neurodevelopmental disorder, observed in 5-10 % of children. Family and twin studies suggest a strong genetic component, but relatively few candidate genes have been reported to date. A recent genome-wide association study (GWAS) described the first statistically significant association specifically for a SLI cohort between a missense variant (rs4280164) in the NOP9 gene and language-related phenotypes under a parent-of-origin model. Replications of these findings are particularly challenging because the availability of parental DNA is required., Methods: We used two independent family-based cohorts characterised with reading- and language-related traits: a longitudinal cohort (n = 106 informative families) including children with language and reading difficulties and a nuclear family cohort (n = 264 families) selected for dyslexia., Results: We observed association with language-related measures when modelling for parent-of-origin effects at the NOP9 locus in both cohorts: minimum P = 0.001 for phonological awareness with a paternal effect in the first cohort and minimum P = 0.0004 for irregular word reading with a maternal effect in the second cohort. Allelic and parental trends were not consistent when compared to the original study., Conclusions: A parent-of-origin effect at this locus was detected in both cohorts, albeit with different trends. These findings contribute in interpreting the original GWAS report and support further investigations of the NOP9 locus and its role in language-related traits. A systematic evaluation of parent-of-origin effects in genetic association studies has the potential to reveal novel mechanisms underlying complex traits.

We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P < 0.5 × 10(-8)) for a relative hand skill measure in individuals with dyslexia. PCSK6 activates Nodal, a morphogen involved in regulating left-right body axis determination. Therefore, the GWAS data suggest that the biology underlying the patterning of structural asymmetries may also contribute to behavioural laterality, e.g. handedness. The association is further supported by an independent study reporting a variable number tandem repeat (VNTR) within the same PCSK6 locus to be associated with degree of handedness in a general population cohort. Here, we have conducted a functional analysis of the PCSK6 locus combining further genetic analysis, in silico predictions and molecular assays. We have shown that the previous GWAS signal was not tagging a VNTR effect, suggesting that the two markers have independent effects. We demonstrated experimentally that one of the top GWAS-associated markers, rs11855145, directly alters the binding site for a nuclear factor. Furthermore, we have shown that the predicted regulatory region adjacent to rs11855415 acts as a bidirectional promoter controlling the expression of novel RNA transcripts. These include both an antisense long non-coding RNA (lncRNA) and a short PCSK6 isoform predicted to be coding. This is the first molecular characterization of a handedness-associated locus that supports the role of common variants in non-coding sequences in influencing complex phenotypes through gene expression regulation., (© The Author 2016. Published by Oxford University Press.)

Dyslexia is a common condition affecting up to 10% school-aged children. There is strong evidence that genetics plays an important role in dyslexia and is expected to be complex in nature. Few specific susceptibility factors have been identified so far, but their functional characterization has provided novel insights into the biology of dyslexia. In particular, they point to an unexpected role of candidate genes for dyslexia in the biology of cilia, cellular organelles required in many processes including the establishment of left-right asymmetries early in development. This observation has brought back into the spotlight the old idea of a link between dyslexia and handedness. Yet much of the genetics contributing to dyslexia remains unexplained. The lack of biological markers, clear diagnostic criteria, and homogeneous assessment strategies are just some of the factors preventing the collection of the cohorts powered enough for large-scale genetic studies. While the technology and methods to generate and handle large-scale data have reached unprecedented potential, the main challenge remains in establishing universal guidelines to collect suitable phenotype information across independent studies. These difficulties reflect the complex nature of dyslexia which is highly heterogeneous and often co-occurs with other neurodevelopmental disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A significant proportion of children (up to 7% in the UK) present with pronounced language difficulties that cannot be explained by obvious causes like other neurological and medical conditions. A substantial genetic component is predicted to underlie such language problems. Copy number variants (CNVs) have been implicated in neurodevelopmental and psychiatric conditions, such as autism and schizophrenia, but it is not fully established to what extent they might contribute to language disorders. We conducted a CNV screen in a longitudinal cohort of young children with language-related difficulties (n = 85), focusing on single events at candidate loci. We detected a de novo deletion on chromosome 15q13.1-13.3. The adjacent 15q11-13.1 locus is disrupted in Prader-Willi and Angelman syndromes, while disruptions across the breakpoints (BP1-BP6) have previously been implicated in different neurodevelopmental phenotypes including autism, intellectual disability (ID), seizures and developmental delay (DD). This is the first report of a deletion at BP3-BP5 being linked to a deficit confined to language impairment, in the absence of ID, expanding the range of phenotypes that implicate the chromosome 15q13 locus.

Twin studies indicate that dyscalculia (or mathematical disability) is caused partly by a genetic component, which is yet to be understood at the molecular level. Recently, a coding variant (rs133885) in the myosin-18B gene was shown to be associated with mathematical abilities with a specific effect among children with dyslexia. This association represents one of the most significant genetic associations reported to date for mathematical abilities and the only one reaching genome-wide statistical significance. We conducted a replication study in different cohorts to assess the effect of rs133885 maths-related measures. The study was conducted primarily using the Avon Longitudinal Study of Parents and Children (ALSPAC), (N = 3819). We tested additional cohorts including the York Cohort, the Specific Language Impairment Consortium (SLIC) cohort and the Raine Cohort, and stratified them for a definition of dyslexia whenever possible. We did not observe any associations between rs133885 in myosin-18B and mathematical abilities among individuals with dyslexia or in the general population. Our results suggest that the myosin-18B variant is unlikely to be a main factor contributing to mathematical abilities., (© 2015 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a genome-wide association scan (GWAS) meta-analysis using three richly characterized datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading- and language-related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected P ≈ 10(-7) for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on-going international efforts to identify genes contributing to reading and language skills., (© 2014 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

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.

Reading and language disorders are common childhood conditions that often co-occur with each other and with other neurodevelopmental impairments. There is strong evidence that disorders, such as dyslexia and Specific Language Impairment (SLI), have a genetic basis, but we expect the contributing genetic factors to be complex in nature. To date, only a few genes have been implicated in these traits. Their functional characterization has provided novel insight into the biology of neurodevelopmental disorders. However, the lack of biological markers and clear diagnostic criteria have prevented the collection of the large sample sizes required for well-powered genome-wide screens. One of the main challenges of the field will be to combine careful clinical assessment with high throughput genetic technologies within multidisciplinary collaborations.

The estrogenicity of different batches of red clover (Trifolium pratense L., Fabaceae; RCL) extracts and its relationship with the isoflavone content were assessed by measuring MCF-7 cell proliferation by flow cytometry and propidium iodide staining. RCL extracts were compared to estradiol (E2) and to the main RCL isoflavones biochanin A, daidzein, genistein and formononetin. Isoflavone content in the extracts was assayed by HPLC. E2 and isoflavones increased MCF-7 proliferation in a concentration-dependent fashion, with the following potency order: E2>>>genistein>biochanin A=daidzein>formononetin. Extracts increased MCF-7 proliferation with different potencies, which in four out of five extracts correlated with the ratios 5,7-dihydroxyisoflavones/7-hydroxyisoflavones. The efficacy of all extracts increased with decreasing genistein contents. A solution containing the main isoflavones at the average concentration of RCL extracts increased MCF-7 proliferation with higher potency and steeper concentration-response curve. The effects of E2, of RCL extracts and of the isoflavone solution were inhibited by the estrogen receptor antagonist 4-hydroxytamoxifen. Flow cytometric analysis of MCF-7 proliferation is a suitable bioassay for the estrogenicity of RCL extracts, thus expanding the characterization of individual batches beyond assessment of chemical composition and contributing to improved standardization of quality and activity., (Copyright © 2014 Elsevier B.V. All rights reserved.)