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Cardiomyopathy (CMP) is a heritable disorder. Over 50% of cases are gene-elusive on clinical gene panel testing. The contribution of variants in non-coding DNA elements that result in cryptic splicing and regulate gene expression has not been explored. We analyzed whole-genome sequencing (WGS) data in a discovery cohort of 209 pediatric CMP patients and 1953 independent replication genomes and exomes. We searched for protein-coding variants, and non-coding variants predicted to affect the function or expression of genes. Thirty-nine percent of cases harbored pathogenic coding variants in known CMP genes, and 5% harbored high-risk loss-of-function (LoF) variants in additional candidate CMP genes. Fifteen percent harbored high-risk regulatory variants in promoters and enhancers of CMP genes (odds ratio 2.25, p = 6.70 × 10−7 versus controls). Genes involved in α-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) were most highly enriched for regulatory variants (odds ratio 6.7–58.1). Functional effects were confirmed in patient myocardium and reporter assays in human cardiomyocytes, and in zebrafish CRISPR knockouts. We provide strong evidence for the genomic contribution of functionally active variants in new genes and in regulatory elements of known CMP genes to early onset CMP. This project was supported by the Ted Rogers Centre for Heart Research (SM, JE), the Canadian Institutes of Health Research (PJT 175034) (SM, JE) and by the Canadian Institutes of Health Research (ENP 161429), under the frame of ERA PerMed (SM). SM holds the Heart and Stroke Foundation of Canada & Robert M Freedom Chair in Cardiovascular Science. SWS holds the GlaxoSmithKline Endowed Chair in Genome Sciences at the Hospital for Sick Children and the University of Toronto. PGM holds a Canada Research Chair Tier 2 in Non-coding Disease Mechanisms. PGM acknowledges the support of the Government of Canada’s New Frontiers in Research Fund (NFRF), [NFRFE-2018-01305]. EO holds the Bitove Family Professorship of Adult Congenital Heart Disease. MM holds a Ramon y Cajal grant from the Spanish Ministry of Science and Innovation (RYC-2017-22249). WO is supported by funding from Fundació La Marató (321/C/2019). JB is funded by a Frans Van de Werf fellowship for clinical cardiovascular research, and by a senior clinical investigator fellowship of the FWO Flanders. KM was a National Science Foundation Graduate Research Fellow under grant no. DGE1144152 during the majority of the project. CS is the recipient of a National Health and Medical Research Council (NHMRC) Practitioner Fellowship (1154992). JI is the recipient of an NHMRC Career Development Fellowship (1162929). RDB is the recipient of a New South Wales Health Cardiovascular Disease Senior Scientist Grant. PSD is supported by the DBT/Wellcome Trust- Indian Alliance. We acknowledge the Labatt Family Heart Centre Biobank at the Hospital for Sick Children for access to DNA samples, and The Centre for Applied Genomics at the Hospital for Sick Children for performing WGS. We thank Xiucheng Cui and Emanuela Pannia for performing the zebrafish experiments at the SickKids Zebrafish Genetics and Disease Models Core (CRISPR-Cas9 and gRNA syntheses, zebrafish embryo microinjections, gRNA PCR validation, qRT-PCR, cardiac imaging). This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. We thank members of the ICGC/PCAWG working groups for generating the variant calls used in our case-control burden analyses. Peer Reviewed "Article signat per 38 autors/es: Robert Lesurf, Abdelrahman Said, Oyediran Akinrinade, Jeroen Breckpot, Kathleen Delfosse, Ting Liu, Roderick Yao, Gabrielle Persad, Fintan McKenna, Ramil R. Noche, Winona Oliveros, Kaia Mattioli, Shreya Shah, Anastasia Miron, Qian Yang, Guoliang Meng, Michelle Chan Seng Yue, Wilson W. L. Sung, Bhooma Thiruvahindrapuram, Jane Lougheed, Erwin Oechslin, Tapas Mondal, Lynn Bergin, John Smythe, Shashank Jayappa, Vinay J. Rao, Jayaprakash Shenthar, Perundurai S. Dhandapany, Christopher Semsarian, Robert G. Weintraub, Richard D. Bagnall, Jodie Ingles, Genomics England Research Consortium, Marta Melé, Philipp G. Maass, James Ellis, Stephen W. Scherer & Seema Mital"

AimsCardiomyopathy is a clinically and genetically heterogeneous disorder with age and sex-related differences in severity and outcomes. The aim of our study was to identify age and sex-related differences in the genetic architecture of cardiomyopathy.Methods and ResultsWe analyzed whole genome sequence data from 471 pediatric and 926 adult cardiomyopathy patients from our Heart Centre Biobank and from the Genomics England cohort. Overall yield of rare deleterious coding variants was higher in pediatric compared to adult onset cardiomyopathy, but not different by sex.MYH7, TNNT2, MYL3, andVCLvariants were more frequent in pediatric patients;TTNandOBSCNvariants were more frequent in adult patients, withMYH7(Odds ratio 3.6; CI 2.1-6.3) andOBSCN(Odds ratio 5.5, CI 2.0-21.4) remaining significant after adjusting for multiple testing. Variants in early-onset cardiomyopathy clustered in highly constrained coding regions compared to those in adult patients (p=3.9×10−3). There were also differences between pediatric and adult patients in variant location withinMYH7andTTNgenes. When analyzed by sex, variants in female compared to male patients were in more highly constrained coding regions (p=0.002).ConclusionOur findings highlight under-appreciated genetic differences in early versus late onset cardiomyopathy. Variants in childhood cardiomyopathy and in female patients were in highly constrained coding regions of the genome suggesting greater deleterious effects and strong purifying selection in the general population. Knowledge of the affected gene, variant location within the gene, and variant constraint scores may be useful in predicting early versus late onset cardiomyopathy.

Cardiomyopathy (CMP) is a heritable genetic disorder. Protein-coding variants account for 20-30% of cases. The contribution of variants in non-coding DNA elements that regulate gene expression has not been explored. We performed whole-genome sequencing (WGS) of 228 unrelated CMP families. Besides pathogenic protein-coding variants in known CMP genes, 5% cases harbored rare loss-of-function variants in novel cardiac genes, with NRAP and FHOD3 being strong candidates. WGS also revealed a high burden of high-risk variants in promoters and enhancers of CMP genes in an additional 20% cases (Odds ratio 2.14, 95% CI 1.60-2.86, p=5.26×10−7 vs 1326 controls) with genes involved in α-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) specifically enriched for regulatory variants (False discovery rate

BackgroundAssess process, uptake, validity and resource needs for return of actionable research findings to biobank participants.MethodsParticipants were prospectively enrolled in a multicenter biorepository of childhood onset heart disease. Clinically actionable research findings were reviewed by a Return of Research Results Committee (RRR) and returned to the physician or disclosed directly to the participant through a research genetic counselor. Action taken following receipt of this information was reviewed.ResultsGenetic data was generated in 1963 of 7408 participants. Fifty-nine new findings were presented to the RRR committee; 20 (34%) were deemed reportable. Twelve were returned to the physician, of which 7 were disclosed to participants (median time to disclosure, 192 days). Seven findings were returned to the research genetic counselor; all have been disclosed (median time to disclosure, 19 days). Twelve families (86%) opted for referral to clinical genetics after disclosure of findings; 7 results have been validated, 5 results are pending. Average cost of return and disclosure per reportable finding incurred by the research program was $750 when utilizing a research genetic counselor; clinical costs associated with return were not included.ConclusionsReturn of actionable research findings was faster if disclosed directly to the participant by a research genetic counselor. There was a high acceptability amongst participants for receiving the findings, for referral to clinical genetics, and for clinical validation of research findings, with all referred cases being clinically confirmed.

It has long been held that product developers should not rely solely on instrumental measures of texture. This study examined the widely accepted effects of salivary α amylase on mouth thinning during oral processing. To understand this phenomenon, 13 descriptive panelists were trained to manipulate starch thickened semisolid foods and note when changes in the perceived thickness occurred. The panelists were subsequently grouped based on their reports of how quickly these foods broke down in their oral cavity. The accepted effect of salivary α amylase was then analyzed and found to be consistent across the starch thickened foods examined but different among the panelists. Thus it became clear that starch containing foods with long residence times in the mouth can be perceived differently among people based on their amylase activity, making descriptive profiling difficult to calibrate. This study suggests that classic sensory techniques could also have limitations when considering the oral processing of starchy foods, especially those with long residence times in the oral cavity. Panelists' individual salivary amylase activity was not measured in this study. Practical applications Food texture is an important sensory attribute that affects consumers' acceptance of products. Semisolid foods such as puddings and yogurts are expected to thin as the food is manipulated in the mouth. By the same token, starch systems in chewy candies can also be impacted over long periods of mastication. Understanding the impact of salivary amylase on how quickly these foods breakdown is important to developing foods that will be acceptable to consumers. Developers with an understanding of the effects salivary amylase has on various starches can lead them to design products that perform more consistently across individuals with different activity levels of salivary α amylase.

It has long been held that product developers should not rely solely on instrumental measures of texture. This study examined the widely accepted effects of salivary α amylase on mouth thinning during oral processing. To understand this phenomenon, 13 descriptive panelists were trained to manipulate starch thickened semisolid foods and note when changes in the perceived thickness occurred. The panelists were subsequently grouped based on their reports of how quickly these foods broke down in their oral cavity. The accepted effect of salivary α amylase was then analyzed and found to be consistent across the starch thickened foods examined but different among the panelists. Thus it became clear that starch containing foods with long residence times in the mouth can be perceived differently among people based on their amylase activity, making descriptive profiling difficult to calibrate. This study suggests that classic sensory techniques could also have limitations when considering the oral processing of starchy foods, especially those with long residence times in the oral cavity. Panelists' individual salivary amylase activity was not measured in this study.Food texture is an important sensory attribute that affects consumers' acceptance of products. Semisolid foods such as puddings and yogurts are expected to thin as the food is manipulated in the mouth. By the same token, starch systems in chewy candies can also be impacted over long periods of mastication. Understanding the impact of salivary amylase on how quickly these foods breakdown is important to developing foods that will be acceptable to consumers. Developers with an understanding of the effects salivary amylase has on various starches can lead them to design products that perform more consistently across individuals with different activity levels of salivary α amylase.

BACKGROUND: Consenting minors for genetics research and biobanking involves ethical and social challenges. We examined factors influencing participation rates in a population-based biorepository for childhood heart disease. METHODS: Individuals were prospectively enrolled across 7 centers in Ontario by using a standardized consent form. Individuals were approached for consent for the donation of blood/saliva (DNA), tissue, and skin from the affected individual for future genomics and stem cell research. Consent rates were compared between pediatric and adult patients and factors affecting consent were analyzed by using multiple logistic regression analysis. RESULTS: From 2008 to 2011, 3637 patients were approached. A total of 2717 pediatric patients consented (90% consent rate); mean age was 8.5 ± 5.8 years (57% male; 76% white). A total of 561 adult patients consented (92% consent rate, P = .071 versus pediatric). Factors associated with lower pediatric consent rates included younger age, race, absence of complex defects, and location of consent; these were not associated with adult consent rates. Leading causes for refusal of consent were lack of interest in research (43%), overwhelmed clinically (14%), and discomfort with genetics (11%). Concerns related to privacy, insurability, indefinite storage, and ongoing access to medical records were not the leading causes for refusal. CONCLUSIONS: The high pediatric consent rate (90%) was comparable with that of adults. Ethical, social, or legal issues were not the leading reasons for refusal of consent.

Background: hypoxia-inducible factor (HIF1A) regulates the myocardial response to hypoxia and hemodynamic load. We investigated the association of variants with right-ventricular (RV) remodeling after tetralogy of Fallot (TOF) repair. Methods: children with TOF were genotyped for three single-nucleotide polymorphisms in HIF1A. Genotypes were analyzed for association with RV myocardial protein expression and fibrosis at complete repair (n = 42) and RV dilation, fractional area change, and freedom from pulmonary valve/conduit replacement on follow-up. results: In 180 TOF patients, mean age at repair was 1.0 ± 0.8 y with follow-up at 9.0 ± 3.5 y; 82% had moderate to severe pulmonary insufficiency. Freedom from RV reinterventions at 5, 10, and 15 y was 92, 84, and 67%, respectively. Patients with more functioning HIF1A alleles had higher transforming growth factor β1 expression and more fibrosis at initial repair as compared with controls (P < 0.05). During follow-up, patients with more functioning HIF1A alleles showed less RV dilation, better preservation of RV function, and greater freedom from RV reinterventions (P < 0.05). This was confirmed in a replication cohort of 69 patients. conclusion: In children who have had TOF repair, a lower number of functioning HIF1A alleles was associated with RV dilation and dysfunction, suggesting that hypoxia adaptation in unrepaired TOF may influence RV phenotype after repair.

This article introduces a new attribute called SPICE (spectral imaging of correlative events) that calculates a bed-form boundary framework from the seismic data, and highlights detail from subtle changes in the seismic wavelet. The concept of spectral imaging is presented in the context of a well-log model and its relationship to impedance layering. Further validation of the method is provided by a detailed sequence stratigraphy analysis using well logs and seismic data from the northern Gulf of Mexico. The technique, based on wavelet transform decomposition and singularity analysis of migrated seismic data, uses the localization properties of the wavelet transform in time and frequency to produce a unique display that provides a boundary framework of the subsurface that is rich in structural and stratigraphic detail. This advances seismic interpretation closer to the goal of producing accurate geologic mapping of the subsurface. Additionally, this attribute offers a straightforward way to interpret a seismic section similar to a geologist in the field who maps beds and faults directly from the outcrop. Most seismic interpretation today is performed on variable area displays of the seismic amplitude of a wavelet that changes with depth. This has historically posed a number of significant problems for the interpreter. Reflections in seismic data are blurred representations of the actual stratigraphy. The interference of a changing pulse shape with a wide variety of impedance contrasts in the subsurface adds a significant element of uncertainty to the final mapping of reservoir, seal, and trap. The richness and nonstationary character of the seismic trace require a process that localizes rapidly changing features in the spectrum. The unique calculation reduces the uncertainty in picking subtle bed-form boundaries and brings out the full extent of the resolution of the seismic amplitude data. SPICE is computed in the continuous wavelet transform (CWT) domain …

A series of experiments investigated the nature of metallic taste reports and whether they can be attributed to the development of a retronasal smell. Two studies showed that the metallic sensation reports following oral stimulation with solutions of FeSO4 were reduced to baseline when the nose was occluded. No such reduction was seen for CuSO4 or ZnSO4, which were more bitter and astringent, respectively, and less metallic. A discrimination test based on weak but equi-intense levels of FeSO4 and CuSO4 showed that FeSO4 could be discriminated from water with the nose open but not when occluded, but that discrimination of CuSO4 from water was not impaired by nasal occlusion. A discrimination test demonstrated that the headspace over solutions of FeSO4 was not different from water, although some subjects could discriminate FeSO4 solutions from water in the mouth when the nose was occluded, perhaps by tactile or astringent cues. These results confirm that metallic taste reports following oral stimulation with FeSO4 are likely due to development of a retronasal smell, possibly following a lipid oxidation reaction in the mouth. However, metallic taste reports may arise from different mechanisms with copper and zinc salts.

Judges rated images of lagers at different stages of consumption displaying various levels of head and lacing. Judges expressed their preference for one of four beer images at each of three stages of consumption. In so doing, judges created a virtual beer “preference path”. Judges then repeated the process as if the exact beer preference path they favored was unavailable, but any of the other 64 possible combinations was available. Judges continued to repeat this procedure until they had selected their top the five beer preference paths. We call this technique the “path analysis method of eliminating preferred stimuli”, or the PAMEPS approach, which allows simultaneous determination of preference among and within stages of consumption. Sampling of Belgian, Finnish, Irish, and Scottish populations reveals no preferences for foam images among stages of beer consumption, but suggest that within different stages of consumption there exist preferences for specific foam types at different geographic localities.

The adsorption behavior and surface excess of an asymmetric poly(styrene)-block-poly(ethylene oxide) copolymer, 4.2% by mass poly(ethylene oxide), from a cyclohexane solution onto a SiO2 surface ar...

The appearance of beer influences the perception of its flavour. Three separate studies were performed. Two studies using United States residents comparing beers ranked for different attributes showed that differences in colour, head and levels of lacing impacted the perception of a number of other attributes. Rankings for best to worst poured, best to worst handled, best to worst brewed, best to worst head, most to least stable foam, highest to lowest quality foam, best to worst overall flavour, best to worst overall appearance, and most to least likely to buy all showed significant differences in rankings for both colour and levels of head and lacing. A third study using Scottish participants, comparing beers differing only in levels of head and lacing complements the American findings, suggesting that the appearance of a beer greatly influences consumer perception.

A method has been explored for assessing hydrophobic polypeptides in beer by measuring fluorescence developed upon interaction of the proteins with 1-anilino-8-naphthalenesulfonate. The method was initially applied to three separate purified proteins (bovine serum albumin, cytochrome c and catalase) and different response patterns were observed, suggesting that a simple picture would not be obtained with a complex polypeptide mixture such as beer. Furthermore substantial interference, including a high level of background fluorescence, was caused by beer components, especially in ales. Use of the method, after reducing interference by dilution or dialysis of the beer, does not appear to confer any additional value over the direct measurement of total protein in beer using Coomassie Blue-binding methods.

PurposeThe purpose of this paper is to explain how opening up decision making to those who can add value helps to transform organizational performance.Design/methodology/approachReveals how this was achieved at a top‐four UK bank. Draws on some of the ideas presented in the author's latest book, The CEO: Chief Engagement Officer.FindingsEmphasizes the difference between flawed internal‐marketing programs, born at the tail‐end of the command‐and‐control era, which simply viewed employees as internal customers who were marketed at as any other “stakeholder group” when plans were afoot to refresh a company's strategy, and modern employee engagement, which involves taking the risk to reach down and engage the people it affects and the people who must deliver the end result.Practical implicationsPresents a toolbox of practical processes that help leaders to take the risk of sharing power, to engage the creativity of their people.Originality/valueAdvances the view that, by empowering leaders and employees to become partners in pushing an organization forward, good engagement planning is the “missing 50 percent” of strategy formulation.

Posits that the context of internal communication is changing rapidly, and that most organizations are seeking to reduce communications. Identifies nine roles of communication, including: cultural conscience, interpreter of ethics, facilitator of re‐visioning and openness, and communication planner. Concludes that communication is vital for future success.

The foremost neoclassical sculptor of his age, Antonio Canova (1757–1822) is best known for his masterpiece The Three Graces, embodying in marble an ideal of feminine beauty. Descended from stonecutters, Canova was apprenticed to the sculptor Giuseppe Bernardi, quickly establishing his reputation for originality through works such as Psyche Revived by Cupid's Kiss. The idealism of his art, moving away from ornate baroque style, did much to increase the popularity of contemporary sculpture, and his skills were greatly acclaimed and in demand during his lifetime. The present work, first published in 1825 by the Scottish minister John Smythe Memes (1795–1858), is one of the many eulogistic works that appeared soon after Canova's death. Opening with a contextualising history of the development of modern sculpture, the book closely studies Canova's body of work and also contains a chronological catalogue of his creations with details of their owners and locations.

Background The healthcare burden related to congenital heart disease ( CHD ) is increasing with improving survival. We assessed changing trends in prenatal risk factors for CHD in the current era in a Canadian cohort. Methods and Results CHD patients ECA s), and antenatal risk factors were assessed. Temporal trends were analyzed and associations with CHD were measured using linear and logistic regression. Family history of CHD and frequency of major ECA s was higher in cases versus controls ( P CHD had a confirmed genetic diagnosis. Yield of genetic testing (ie, frequency of abnormal results) was higher in familial and syndromic cases. There was an increase in parental age at conception, maternal prepregnancy body mass index, maternal urinary tract infections, type 1 diabetes, and exposure to nonfertility medications during pregnancy from 1990–2011. Later year of birth, family history of CHD , presence of major ECA s, maternal smoking during pregnancy, and maternal medication exposure were associated with increased odds of CHD ( P CHD caused by genetic abnormalities. Conclusions The increase in prenatal risk factors for CHD highlights the need for more rigorous ascertainment of genetic and environmental factors including gene‐environment interactions that contribute to CHD .

Posits that the context of internal communication is changing rapidly, and that most organizations are seeking to reduce communications. Identifies nine roles of communication, including: cultural conscience, interpreter of ethics, facilitator of re‐visioning and openness, and communication planner. Concludes that communication is vital for future success.

Some attributes have a solid basis in physics or mathematics and we can term these general attributes. They are robust and can be expected to perform predictably from basin to basin around the world. Of course, like any seismic process they can be rendered useless by severe random or coherent noise, or inappropriate geologic setting. General attributes include horizon peak amplitude and time structure, complex amplitude and frequency, generalized Hilbert attributes, horizon dip and azimuth, illumination, edge-preserved smoothing, edge detection, AVO, coherence, and spectral decomposition. This is not a comprehensive list but should illustrate the class of general attributes. AVO is a good case in point. It is solidly based on the physics of angular elastic reflection coefficients. As workers have applied AVO worldwide they have learned the geologic situations where it is useful and where it is not. This accretion of knowledge is possible because AVO is a robust, physically-based attribute.

Additive technologies able to successfully lubricate gas engines have been available for many years, but in recent years the acceleration of both commercial and technical demands placed on gas engine lubricants has highlighted the performance limits of traditional additive solutions. One of these limits is the ability to reach long and very long oil drains, required by an increasing number of operators. Since traditional additive chemistries on conventional base oil systems have reached their limits in that respect, focus has been increasingly placed on using higher performance base oils so that longer oil drains can be reached. However, traditional additive chemistries have often proved to struggle in these higher performance base oils, particularly in the aspect of deposit control — demonstrating that a new generation of additive systems for the formulation of gas engine oils is needed. The authors present one such generation of additive systems, developed around off-the-beaten-track detergent technology; providing superior control of oxidation and deposits. Such additive systems can be used either in conventional base oil systems with improved drain interval, or in high performance base oil systems with very long drain interval and excellent control of deposits. Besides the description of the chemistry involved, the authors also present a methodology of performance evaluation in the laboratory, and compare this methodology with the performance perceived in the field.Copyright © 2003 by ASME