Medial olivocochlear suppression in musicians versus non-musicians

The medial olivocochlear efferent (MOCE) branch synapses with outer hair cells (OHCs), and the efferent pathway can be activated via a contralateral acoustic stimulus (CAS). The activation of MOCE can change OHC motile responses and convert signals that are capable of controlling the sensitivity of the peripheral hearing system in a frequency-specific manner. The aim of this study was to examine the MOCE system activity in professional musicians using transient evoked otoacoustic emission test and CAS. Musician group showed stronger suppression in all frequency bands in the presence of CAS

Statin treatment effectiveness and the SLCO1B1*5 reduced function genotype: Long-term outcomes in women and men

This is the final version. Available from British Pharmacological Society / Wiley via the DOI in this record. The genetic and phenotypic UK Biobank data are available upon application to the UK Biobank (www.ukbiobank.ac.uk/register-apply). The derived data fields used in our analysis will be available via the UK Biobank, search for application number 14631. We are not able to share these directly.OBJECTIVE: To estimate the effect of rs4149056 (SLCO1B1*5) genotype (decreases statin transport) on cholesterol control and treatment duration in male and female primary care patients prescribed common statin medications. METHODS AND ANALYSIS: This study comprised 69 185 European-ancestry UK Biobank cohort participants prescribed simvastatin or atorvastatin (aged 40-79 years at first prescription, treatment duration 1 month to 29 years, mean 5.7 years). Principal outcomes were clinically high total cholesterol (>5 mmol/L) at baseline, plus treatment discontinuation. RESULTS: A total of 48.4% of 591 females homozygous for SLCO1B1*5 decreased function genotype had raised cholesterol vs 41.7% of those with functioning SLCO1B1 (odds ratio 1.31, 95% confidence interval [CI] 1.1-1.55, P = .001). Fewer males had high cholesterol and the genotype effect was attenuated. In primary care prescribing, females homozygous for SLCO1B1*5 were more likely to stop receiving these statins (29.5%) than women with normal SLCO1B1 (25.7%) (hazard ratio [HR] 1.19, 95% CI 1.03-1.37, P = .01), amounting to five discontinuations per 100 statin-years in the SLCO1B1*5 group vs four in the normal SLCO1B1 function group. This remained significant after the first year of treatment (HR for discontinuing >1 year after first prescription 1.3, 95% CI 1.08-1.56, P = .006). In men SLCO1B1*5 was only associated with treatment discontinuation in the first year. CONCLUSIONS: In this large community sample of patients on commonly prescribed statins, the SLCO1B1*5 decreased function variant had much larger effects on cholesterol control and treatment duration in women than in men. Efforts to improve the effectiveness of statin therapy in women may need to include SLCO1B1*5 genotype-guided statin selection.National Institute for Health ResearchMinistry of National Education, Republic of TurkeyExpanding Excellence in EnglandUniversity of Exeter Medical Schoo

CA8 Mutations Cause a Novel Syndrome Characterized by Ataxia and Mild Mental Retardation with Predisposition to Quadrupedal Gait

We describe a consanguineous Iraqi family in which affected siblings had mild mental retardation and congenital ataxia characterized by quadrupedal gait. Genome-wide linkage analysis identified a 5.8 Mb interval on chromosome 8q with shared homozygosity among the affected persons. Sequencing of genes contained in the interval revealed a homozygous mutation, S100P, in carbonic anhydrase related protein 8 (CA8), which is highly expressed in cerebellar Purkinje cells and influences inositol triphosphate (ITP) binding to its receptor ITPR1 on the endoplasmatic reticulum and thereby modulates calcium signaling. We demonstrate that the mutation S100P is associated with proteasome-mediated degradation, and thus presumably represents a null mutation comparable to the Ca8 mutation underlying the previously described waddles mouse, which exhibits ataxia and appendicular dystonia. CA8 thus represents the third locus that has been associated with quadrupedal gait in humans, in addition to the VLDLR locus and a locus at chromosome 17p. Our findings underline the importance of ITP-mediated signaling in cerebellar function and provide suggestive evidence that congenital ataxia paired with cerebral dysfunction may, together with unknown contextual factors during development, predispose to quadrupedal gait in humans

Analysis of CYP2C19 genetic variants with ischaemic events in UK patients prescribed clopidogrel in primary care: a retrospective cohort study.

This is the final version. Available from BMJ Publishing Group via the DOI in this record. Data availability statement: Data may be obtained from a third party and are not publicly available. Data are available on application to the UK Biobank ( www.ukbiobank.ac.uk/register-apply). Additional data are available from the corresponding author on reasonable request.OBJECTIVE: To determine whether CYP2C19 loss-of-function (LoF) alleles increase risk of ischaemic stroke and myocardial infarction (MI) in UK primary care patients prescribed clopidogrel. DESIGN: Retrospective cohort analysis. SETTING: Primary care practices in the UK from January 1999 to September 2017. PARTICIPANTS: 7483 European-ancestry adults from the UK Biobank study with genetic and linked primary care data, aged 36-79 years at time of first clopidogrel prescription. INTERVENTIONS: Clopidogrel prescription in primary care, mean duration 2.6 years (range 2 months to 18 years). MAIN OUTCOME MEASURE: Hospital inpatient-diagnosed ischaemic stroke, MI or angina while treated with clopidogrel. RESULTS: 28.7% of participants carried at least one CYP2C19 LoF variant. LoF carriers had higher rates of incident ischaemic stroke while treated with clopidogrel compared with those without the variants (8 per 1000 person-years vs 5.2 per 1000 person-years; HR 1.53, 95% CIs 1.04 to 2.26, p=0.031). LoF carriers also had increased risk of MI (HR 1.14, 95% CI 1.04 to 1.26, p=0.008). In combined analysis LoF carriers had increased risk of any ischaemic event (stroke or MI) (HR 1.17, 95% CI 1.06 to 1.29, p=0.002). Adjustment for aspirin coprescription produced similar estimates. In lifetables using observed incidence rates, 22.5% (95% CI 14.4% to 34.0%) of CYP2C19 LoF carriers on clopidogrel were projected to develop an ischaemic stroke by age 79 (oldest age in the study), compared with 15.4% (95% CI 11.4% to 20.5%) in non-carriers, that is, 7.1% excess stroke incidence in LoF carriers by age 79. CONCLUSIONS: A substantial proportion of the UK population carry genetic variants that reduce metabolism of clopidogrel to its active form. In family practice patients on clopidogrel, CYP2C19 LoF variants are associated with substantially higher incidence of ischaemic events. Genotype-guided selection of antiplatelet medications may improve outcomes in patients carrying CYP2C19 genetic variants.Medical Research CouncilAlzheimer’s SocietyNational Institute for Health ResearchUniversity of Exeter Medical SchoolUniversity of Connecticut School of MedicineMinistry of National Education, Republic of TurkeyTravelers Chair in Geriatrics and GerontologyNational Institute on Agin

Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes

Structural variants are a common cause of disease and contribute to a large extent to inter-individual variability, but their detection and interpretation remain a challenge. Here, we investigate 11 individuals with complex genomic rearrangements including germline chromothripsis by combining short- and long-read genome sequencing (GS) with Hi-C. Large-scale genomic rearrangements are identified in Hi-C interaction maps, allowing for an independent assessment of breakpoint calls derived from the GS methods, resulting in >300 genomic junctions. Based on a comprehensive breakpoint detection and Hi-C, we achieve a reconstruction of whole rearranged chromosomes. Integrating information on the three-dimensional organization of chromatin, we observe that breakpoints occur more frequently than expected in lamina-associated domains (LADs) and that a majority reshuffle topologically associating domains (TADs). By applying phased RNA-seq, we observe an enrichment of genes showing allelic imbalanced expression (AIG) within 100 kb around the breakpoints. Interestingly, the AIGs hit by a breakpoint (19/22) display both up- and downregulation, thereby suggesting different mechanisms at play, such as gene disruption and rearrangements of regulatory information. However, the majority of interpretable genes located 200 kb around a breakpoint do not show significant expression changes. Thus, there is an overall robustness in the genome towards large-scale chromosome rearrangements

Masonry compressive strength prediction using artificial neural networks

The masonry is not only included among the oldest building materials, but it is also the most widely used material due to its simple construction and low cost compared to the other modern building materials. Nevertheless, there is not yet a robust quantitative method, available in the literature, which can reliably predict its strength, based on the geometrical and mechanical characteristics of its components. This limitation is due to the highly nonlinear relation between the compressive strength of masonry and the geometrical and mechanical properties of the components of the masonry. In this paper, the application of artificial neural networks for predicting the compressive strength of masonry has been investigated. Specifically, back-propagation neural network models have been used for predicting the compressive strength of masonry prism based on experimental data available in the literature. The comparison of the derived results with the experimental findings demonstrates the ability of artificial neural networks to approximate the compressive strength of masonry walls in a reliable and robust manner.- (undefined