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Genomic medicine holds great promise for improving health care, but integrating searchable and actionable genetic data into electronic health records (EHRs) remains a challenge. Here we describe Neptune, a system for managing the interaction between a clinical laboratory and an EHR system during the clinical reporting process. We developed Neptune and applied it to two clinical sequencing projects that required report customization, variant reanalysis, and EHR integration. Neptune has been applied for the generation and delivery of over 15,000 clinical genomic reports. This work spans two clinical tests based on targeted gene panels that contain 68 and 153 genes respectively. These projects demanded customizable clinical reports that contained a variety of genetic data types including single-nucleotide variants (SNVs), copy-number variants (CNVs), pharmacogenomics, and polygenic risk scores. Two variant reanalysis activities were also supported, highlighting this important workflow. Methods are needed for delivering structured genetic data to EHRs. This need extends beyond developing data formats to providing infrastructure that manages the reporting process itself. Neptune was successfully applied on two high-throughput clinical sequencing projects to build and deliver clinical reports to EHR systems. The software is open source and available at https://gitlab.com/bcm-hgsc/neptune .

Retinoic acid exposures as well as defects in the retinoic acid-degrading enzyme CYP26B1 have teratogenic effects on both limb and craniofacial skeleton. An initial report of four individuals described a syndrome of fetal and infantile lethality with craniosynostosis and skeletal anomalies caused by homozygous pathogenic missense variants in CYP26B1. In contrast, a 22-year-old female was reported with a homozygous missense pathogenic variant in CYP26B1 with complex multisuture craniosynostosis and intellectual disability, suggesting that in some cases, biallelic pathogenic variants of CYP26B1 may be compatible with life. Here we describe four additional living individuals from two families with compound heterozygous pathogenic missense variants in CYP26B1. Structural assessment of these additional missense variants places them further from the catalytic site and supports a model consistent with milder nonlethal disease. In addition to previously reported findings of multisuture craniosynostosis, conductive hearing loss, joint contractures, long slender fingers, camptodactly, broad fingertips, and developmental delay/intellectual disability, skeletal imaging in our cases also revealed gracile long bones, gracile ribs, radioulnar synostosis, and carpal and/or tarsal fusions. These individuals broaden the phenotypic range of biallelic pathogenic variants in CYPB26B1 and most significantly clarify that mortality can range from perinatal lethality to survival into adulthood.

The RASopathies are a group of similar genetic syndromes with cardiovascular abnormalities, characteristic facial features, short stature, abnormalities of the skin and musculoskeletal system, and variable neurodevelopmental challenges. The most common cardiovascular abnormalities include pulmonary valvular stenosis and hypertrophic cardiomyopathy. Congenital polyvalvular disease (CPVD) refers to congenital dysplasia of two or more cardiac valves. We diagnosed a RASopathy in two individuals with CPVD and noted that CPVD in RASopathies has rarely been reported in the literature. Thus, we performed a retrospective chart review and literature review to investigate the association and characterize the phenotype of CPVD in the RASopathies. CPVD was present in 2.5% (n = 6/243) of individuals in our RASopathy cohort. Involvement of two cardiac valves, commonly the aortic and pulmonic valves, was seen in the majority of individuals (6/8; 75%) in our cohort, but only 27% (3/11) of reported CPVD and RASopathy cases in the literature. CPVD should be considered an associated cardiovascular phenotype of the RASopathies, which has implications for diagnosis and management.

PURPOSE: Pediatric cardiomyopathy is rare, has a broad differential diagnosis, results in high morbidity and mortality, and has sub-optimal diagnostic yield using next generation sequencing panels. Exome sequencing has reported diagnostic yields ranging from 30-57% for neonates in intensive care units. We aimed to characterize the clinical utility of exome sequencing in infantile heart failure. METHODS: Infants diagnosed with acute heart failure prior to 1 year old over a period of 34 months at a large tertiary children’s hospital were recruited. Demographic and diagnostic information was obtained from medical records. Fifteen eligible patients were enrolled. RESULTS: Dilated cardiomyopathy was the predominant cardiac diagnosis, seen in 60% of patients. Molecular diagnosis was identified in 66.7% of patients (10/15). Of those diagnoses, 70% would not have been detected using multi-gene next generation sequencing panels focused on cardiomyopathy or arrhythmia disease genes. Genetic testing changed medical decision-making in 53% of all cases and 80% of positive cases, and was especially beneficial when testing was expedited. CONCLUSIONS: Given the broad differential diagnosis and critical status of infants with heart failure, rapid exome sequencing provides timely diagnoses, changes medical management, and should be the first-tier molecular test.

In this digital era, consumers are influenced by various intelligent computing technologies in the age of the Internet of Things (IoT) to enhance their comfort and quality of life. A Smart TV with broadcasting services is considered as an excellent illustration of the digital technologies. Smart TV applications and software are constantly developed, and it has been certified to satisfy EAL2 security requirements. These technologies understand hand movements and responds appropriately. They are, however, vulnerable to security breaches via email, cameras, internet connectivity, and media players. However, the risks can be reduced by utilizing passwords, antivirus software, secure Wi-Fi, and other methods. This research study is a review on the applications of Smart TV in an IoT driven environment. The purpose of this research is to develop and describe: (a) study architecture, (b) working (c) security issues, (d) testing, (e) advantages and (f) disadvantages.

The advancement of precision medicine requires new methods to coordinate and deliver genetic data from heterogeneous sources to physicians and patients. The eMERGE III Network enrolled >25,000 participants from biobank and prospective cohorts of predominantly healthy individuals for clinical genetic testing to determine clinically actionable findings. The network developed protocols linking together the 11 participant collection sites and 2 clinical genetic testing laboratories. DNA capture panels targeting 109 genes were used for testing of DNA and sample collection, data generation, interpretation, reporting, delivery, and storage were each harmonized. A compliant and secure network enabled ongoing review and reconciliation of clinical interpretations, while maintaining communication and data sharing between clinicians and investigators. A total of 202 individuals had positive diagnostic findings relevant to the indication for testing and 1,294 had additional/secondary findings of medical significance deemed to be returnable, establishing data return rates for other testing endeavors. This study accomplished integration of structured genomic results into multiple electronic health record (EHR) systems, setting the stage for clinical decision support to enable genomic medicine. Further, the established processes enable different sequencing sites to harmonize technical and interpretive aspects of sequencing tests, a critical achievement toward global standardization of genomic testing. The eMERGE protocols and tools are available for widespread dissemination.

Novel gene-disease discoveries, rapid advancements in technology, and improved bioinformatics tools all have the potential to yield additional molecular diagnoses through the reanalysis of exome sequencing data. Collaborations between clinical laboratories, ordering physicians, and researchers are also driving factors that can contribute to these new insights. Automation in ongoing natural history collection, evolving phenotype updates, advancements in processing next-generation sequencing data, and up-to-date variant-gene-disease databases are increasingly needed for systematic exome reanalysis. Here, we review some of the advantages and challenges for clinician-initiated and laboratory-initiated exome reanalysis, and we propose a model for the future that could potentially maximize the clinical utility of exome reanalysis by integrating information from electronic medical records and knowledge databases into routine clinical workflows.

Social Media is an ever-growing tool which will only continue to grow as time goes by. As the commercial applications of social media increase exponentially, interest in using AI techniques to predict the performance of posts has also increased. In this paper we have discussed four major approaches and methodologies to analyse the information present in social media posts and on the basis of the historical data obtained, predict the popularity of any future post in terms of number of likes, comments and shares. These approaches include Deep Neural Network (DNN), Multimodal approach by using the multimodal information embedded in a social media post on a given social media platform, Social Network Services (SNS) for the collection and inference of user-related data and Social Forecast method for the accurate forecast of popularity of content put up on a social media platform. All these methodologies are performed on a dataset in the form of algorithms to obtain results of predictions. These methods take into consideration textual and multimedia content such as images and videos and on the basis of data acquired from these, eventually draw results. Our hope is that this paper can provide an insight into the current state of ML approaches towards social media metrics prediction.

Coronavirus has significantly entered the globe and has affected everyone’s life in some form or another. The identification of the coronavirus is as important as prevention. An early and precise diagnosis will have significant-good benefits for us. The Convolutional Neural Network can be implemented for virus detection, and content-adaptive progressive occlusion analysis could be used to handle occlusion. To improve precision, it is also possible to add many other classification methods accordingly, which are mentioned in this paper.

International audience; Purpose:CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype.Methods:We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations.Results:Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism.Conclusion:We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.

Carrier screening involves detection of carrier status for genes associated with recessive conditions. A negative carrier screening test result bears a nonzero residual risk (RR) for the individual to have an affected child. The RR depends on the prevalence of specific conditions and the detection rate (DR) of the test itself. Herein, we provide a detailed approach for calculating DR and RR. DR was calculated on the basis of the sum of disease allele frequencies (DAFs) of pathogenic variants found in published literature. As a proof of concept, DAF data for cystic fibrosis were compared with society guidelines. The DAF data calculated by this method were consistent with the published cystic fibrosis guideline. In addition, we compared DAF for four genes (ABCC8, ASPA, GAA, and MMUT) across three laboratories, and outlined the likely reasons for discrepancies between these laboratories. The utility of carrier screening is to support couples with information while making reproductive choices. Accurate development of DR and RR is therefore critical. The method described herein provides an unbiased and transparent process to collect, calculate, and report these data.

As the human brain transforms incoming sounds, it remains unclear whether semantic meaning is assigned via distributed, domain-general architectures or specialized hierarchical streams. Here we show that the spatiotemporal progression from acoustic to semantically dominated representations is consistent with a hierarchical processing scheme. Combining magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) patterns, we found superior temporal responses beginning ~80 ms post-stimulus onset, spreading to extratemporal cortices by ~130 ms. Early acoustically-dominated representations trended systematically toward semantic category dominance over time (after ~200 ms) and space (beyond primary cortex). Semantic category representation was spatially specific: vocalizations were preferentially distinguished in temporal and frontal voice-selective regions and the fusiform face area; scene and object sounds were distinguished in parahippocampal and medial place areas. Our results are consistent with an extended auditory processing hierarchy in which acoustic representations give rise to multiple streams specialized by category, including areas typically considered visual cortex.

Purpose Hearing loss (HL) is the most common sensory disorder in children. Prompt molecular diagnosis may guide screening and management; especially in syndromic cases when HL is the single presenting feature. Exome sequencing (ES)is an appealing diagnostic tool for HL as the genetic causes are highly heterogeneous. Methods ES was performed on a prospective cohort of 43 probands with HL. Sequence data were analyzed for primary and secondary findings. Capture and coverage analysis was performed for genes and variants associated with HL. Results The diagnostic rate using ES was 37.2% compared to 15.8% with clinical HL panel. Secondary findings were discovered in three patients. For 247 genes associated with HL, 94.7% of the exons were targeted for capture and 81.7% of these exons were covered at 20× or greater. Further analysis of 454 randomly selected HL-associated variants showed 89% were targeted for capture and 75% were covered at a read depth of at least 20×. Conclusion ES has an improved yield to clinical testing and may capture diagnoses not initially considered due to subtle clinical phenotypes. Technical challenges were identified, including inadequate capture and coverage of HL genes. Additional considerations of ES include secondary findings, cost, and turnaround time.

ClinVar provides open access to variant classifications shared from many clinical laboratories. While most classifications are consistent across laboratories, classification differences exist. To facilitate resolution of classification differences on a large scale, clinical laboratories were encouraged to reassess outlier classifications of variants with medically significant differences. Outliers were identified by first comparing ClinVar submissions from 41 clinical laboratories to detect variants with medically significant differences between the laboratories (650 variants). Next, medically significant differences were filtered for variants with ≥3 classifications (244 variants), of which 87.6% (213 variants) had a majority consensus in ClinVar, thus allowing for identification of outlier classifications in need of reassessment. Laboratories with outlier classifications were sent a custom report and encouraged to reassess variants. Results were returned for 204 (96%) variants, of which 62.3% (127) were resolved. Of those 127, 64.6% (82) were resolved due to reassessment prompted by this study and 35.4% (45) resolved by a previously completed reassessment. This study demonstrates a scalable approach to classification resolution and capitalizes on the value of data sharing within ClinVar. These activities will help the community move toward more consistent variant classifications which will improve the care of patients with, or at risk for, genetic disorders.

Xia-Gibbs syndrome (XGS) is a recently described neurodevelopmental disorder due to heterozygous loss-of-function AHDC1 mutations. XGS is characterized by global developmental delay, intellectual disability, hypotonia, and sleep abnormalities. Here we report the clinical phenotype of five of six individuals with XGS identified prospectively at the Children's Hospital of Philadelphia, a tertiary children's hospital in the USA. Although all five patients demonstrated common clinical features characterized by developmental delay and characteristic facial features, each of our patients showed unique clinical manifestations. Patient one had craniosynostosis; patient two had sensorineural hearing loss and bicuspid aortic valve; patient three had cutis aplasia; patient four had soft, loose skin; and patient five had a lipoma. Differential diagnoses considered for each patient were quite broad, and included craniosynostosis syndromes, connective tissue disorders, and mitochondrial disorders. Exome sequencing identified a heterozygous, de novo AHDC1 loss-of-function mutation in four of five patients; the remaining patient has a 357kb interstitial deletion of 1p36.11p35.3 including AHDC1. Although it remains unknown whether these unique clinical manifestations are rare symptoms of XGS, our findings indicate that the diagnosis of XGS should be considered even in individuals with additional non-neurological symptoms, as the clinical spectrum of XGS may involve such non-neurological manifestations. Adding to the growing literature on XGS, continued cohort studies are warranted in order to both characterize the clinical spectrum of XGS as well as determine standard of care for patients with this diagnosis.

Introduction Increased ocular hypertension is one of the main characteristics of glaucoma. Monatepil belongs to a class of calcium channel blockers with special characteristic of α1-adrenergic receptor blocking effect. Calcium channel blockers and α1-adrenergic receptor blocker act as antihypertensive agents. Aim Monatepil has been studied for its effect on ocular hypertension in experimental glaucoma and for its mechanism of action for effect in glaucoma. Material and methods After pretreatment with topical monatepil (1%), 5% dextrose has been administered intravenously through marginal ear vein in healthy New Zealand white rabbits. Pilocarpine (1%) was used as the reference standard. Freshly prepared 50 units of α-chymotrypsin was injected in the posterior chamber of the eye to induce chronic model of glaucoma. After achievement of steady ocular hypertension, single dose treatment with monatepil (1%) and pilocarpine (1%) was given. To find possible mechanism of action, interaction of monatepil with pilocarpine and indomethacin has been studied. Results and discussion Topical administration of monatepil prevented acute increase in intraocular pressure. Monatepil (1%) and pilocarpine (1%) produced a significant decrease in intraocular pressure in α-chymotrypsin induced chronic ocular hypertensive rabbits. Indomethacin (1%) and pilocarpine (1%) pretreatment did not alter intraocular pressure lowering effect of monatepil. Conclusions Monatepil give beneficial effect in ocular hypertension by enhancement of aqueous humor outflow.

RASopathies include disorders generally characterized by developmental delay, specific heart defects, short stature, cardiac hypertrophy, and facial dysmorphisms. Next-generation sequencing (NGS)-based panels have widespread acceptance as a diagnostic tool for RASopathies. The first 126 patients evaluated by clinical examination and the NGS RASopathy panel at the Children’s Hospital of Philadelphia were enrolled. We calculated diagnosis rate, correlated reported clinical findings with positive or negative test results, and identified final molecular diagnoses in 28/96 patients who tested negative for RASopathies. Twenty-four patients had pathogenic variants on the RASopathy panel, for a diagnostic yield of 19%. Reported features of pulmonic stenosis and ptosis were significantly correlated with a positive test result; no reported features were significantly correlated with a negative test result. We identified 27 different alternative diagnoses for patients originally suspected of having RASopathies. This study provides information that can assist in guiding differential diagnosis and genetic testing for patients suspected of having a RASopathy disorder. Genet Med advance online publication 20 October 2016

Cinnarizine, is approved for nausea, vomiting, motion sickness, inner ear disorders and is considered as first-line pharmacotherapy for management of vertigo. It acts by anti-vasoconstrictor activity, reducing blood viscosity and reducing nystagmus in labyrinth. Lack of adequate literature on clinical evidence of cinnarizine and its combination (dimenhydrinate) in vertigo management prompted this review. A specific MEDLINE literature search strategy was designed combining Medical Subject Headings, free-text keywords (like cinnarizine and vertigo) using Boolean operators (1970–2016) for clinical studies, clinical reviews and meta-analyses of cinnarizine. Analyses of studies validated cinnarizine’s efficacy in peripheral and central vertigo versus placebo or other therapies, and was well-tolerated by the patients recruited across different studies. Cinnarizine and/ or its combinations are favorable in management of vestibular disorders wherein cinnarizine acts predominantly peripherally on labyrinth and dimenhydrinate acts centrally on vestibular nuclei and associated centers in brainstem. Combination therapy of cinnarizine and/ or its combinations demonstrated a better safety profile than either of the mono-components, offering a viable therapeutic option in vertigo management.

This work describes SenseCityVity, an approach to engage and support youth in a city in Mexico as they investigate, document, and reflect upon urban problems through mobile crowdsourcing. SenseCityVity focused on the development of a mobile crowdsourcing platform; the deployment of the Urban Data Challenge, codesigned by the authors' research team and actors to collect geolocalized images, audio, and video; and the analysis, appropriation, and creative use of the collected data for community reflection and artistic creation. The approach integrates mobile technology and community practices involving a large population of young people for urban engagement. The collective action generated a new multimedia dataset that is rich in terms of content and is enabling a number of studies aimed at better understanding the urban landscape of cities in the Global South. This article is part of a special issue on smart cities.

Muenke syndrome (MIM #602849), the most common syndromic craniosynostosis, results from the recurrent pathogenic p.P250R variant in FGFR3. Affected patients exhibit wide phenotypic variability. Common features include coronal craniosynostosis, hearing loss, carpal and tarsal anomalies, and developmental/behavioral issues. Our study examined the phenotypic findings, medical management, and surgical outcomes in a cohort of 26 probands with Muenke syndrome identified at the Children’s Hospital of Philadelphia. All probands had craniosynostosis; 69.7% had bicoronal synostosis only, or bicoronal and additional suture synostosis. Three male patients had autism spectrum disorder. Recurrent ear infections were the most common comorbidity, and myringotomy tube placement the most common extracranial surgical procedure. Most patients (76%) required only one fronto-orbital advancement. de novo mutations were confirmed in 33% of the families in which proband and both parents were genetically tested, while in the remaining 66% one of the parents was a mutation carrier. In affected parents, 40% had craniosynostosis, including 71% of mothers and 13% of fathers. We additionally analyzed the medical resource utilization of probands with Muenke syndrome. To our knowledge, these data represent the first comprehensive examination of long-term management in a large cohort of patients with Muenke syndrome. Our study adds valuable information regarding neuropsychiatric and medical comorbidities, and highlights findings in affected relatives.

Social media provides opportunities to examine urban phenomena at scale, and we believe that studying cities in the Global South through citizen-contributed data and AI-driven analytics should be a priority of multimedia research. However, little work has been done in our community, and we argue that this contributes to a double blind side problem. We exemplify this situation by studying Ma3Route, a mobile social media channel to crowdsource and broadcast transit reports in Nairobi, Kenya. Using multimedia data from its Twitter stream, we first conduct a descriptive analysis that shows an active community generating rich traffic-related reports, and then discover latent topics that identify both regular and ephemeral thematic clusters of reports involving accidents, traffic conditions, and attitudes of citizens towards authorities. In the second place, we conduct a deep learning-based analysis of Ma3Route images to understand the kind of visual content shared in the platform, and that shows limitations of using deep neural network models trained with data largely coming from the US and Europe, which do not fully match the reality and diversity of other world regions. We conclude by presenting a multidisciplinary research agenda for future work in this domain.

Next-generation sequencing (NGS) is now routinely used to interrogate large sets of genes in a diagnostic setting. Regions of high sequence homology continue to be a major challenge for short-read technologies and can lead to false-positive and false-negative diagnostic errors. At the scale of whole-exome sequencing (WES), laboratories may be limited in their knowledge of genes and regions that pose technical hurdles due to high homology. We have created an exome-wide resource that catalogs highly homologous regions that is tailored toward diagnostic applications. This resource was developed using a mappability-based approach tailored to current Sanger and NGS protocols. Gene-level and exon-level lists delineate regions that are difficult or impossible to analyze via standard NGS. These regions are ranked by degree of affectedness, annotated for medical relevance, and classified by the type of homology (within-gene, different functional gene, known pseudogene, uncharacterized noncoding region). Additionally, we provide a list of exons that cannot be analyzed by short-amplicon Sanger sequencing. This resource can help guide clinical test design, supplemental assay implementation, and results interpretation in the context of high homology. Genet Med 18 12, 1282–1289.

This communication shares insights into the definition of disease progression and drug durability in type 2 diabetes. Disease progression may be defined as gradual worsening of beta-cell function, clinically observed as an increase in drug dosage, drug frequency or number of glucose lowering drugs needed to maintain HbA1c control; and/or a ≥0.5% rise in HbA1c, unexplained by acute, modifiable factors, while using the same drug regimen; and/or as the occurrence or worsening of cardiovascular or microvascular complications, in spite of standard care, over a pre-specified time period. Durability of a drug or a drug combination may be defined as its ability to postpone or delay progression of disease, in a safe and well tolerated manner. Thus, all drugs that are able to prevent disease progression (i.e., postpone loss of glycaemic control, need for intensification of therapy or onset or worsening of complications) may be termed ‘durable’.

Clinical exome sequencing (CES) has become the preferred diagnostic platform for complex pediatric disorders with suspected monogenic etiologies. Despite rapid advancements, the major challenge still resides in identifying the casual variants among the thousands of variants detected during CES testing, and thus establishing a molecular diagnosis. To improve the clinical exome diagnostic efficiency, we developed Phenoxome, a robust phenotype-driven model that adopts a network-based approach to facilitate automated variant prioritization. Phenoxome dissects the phenotypic manifestation of a patient in concert with their genomic profile to filter and then prioritize variants that are likely to affect the function of the gene (potentially pathogenic variants). To validate our method, we have compiled a clinical cohort of 105 positive patient samples that represent a wide range of genetic heterogeneity. Phenoxome identifies the causative variants within the top 5, 10, or 25 candidates in more than 50%, 71%, or 88% of these exomes, respectively. Furthermore, we show that our method is optimized for clinical testing by outperforming the current state-of-art method. We have demonstrated the performance of Phenoxome using a clinical cohort and showed that it enables rapid and accurate interpretation of clinical exomes. Phenoxome is available at https://phenoxome.chop.edu/ .

IF 3.269; International audience; Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.

Clinical exome sequencing (CES) has become the preferred diagnostic platform for complex pediatric disorders with suspected monogenic etiologies, solving up to 20%-50% of cases depending on indication. Despite rapid advancements in CES analysis, the major challenge still resides in identifying the casual variants among the thousands of variants detected during CES testing, and thus establishing a molecular diagnosis. To improve the clinical exome diagnostic efficiency, we developed Phenoxome, a robust phenotype-driven model that adopts a network-based approach to facilitate automated variant prioritization and subsequent classification. Phenoxome dissects the phenotypic manifestation of a patient in conjunction with their genomic profile to filter and then prioritize putative pathogenic variants. To validate our method, we have compiled a clinical cohort of 105 positive patient samples (i.e. at least one reported ‘pathogenic’ variant) that represent a wide range of genetic heterogeneity from The Children’s Hospital of Philadelphia. Our approach identifies the causative variants within the top 5, 10, or 25 candidates in more than 50%, 71%, or 88% of these patient samples respectively. Furthermore, we show that our method is optimized for clinical testing by yielding superior ranking of the pathogenic variants compared to current state-of-art methods. The web application of Phenoxome is available to the public at http://phenoxome.chop.edu/.

We address the question of what visual cues, including scene objects and demographic attributes, contribute to the automatic inference of perceived ambiance in social media venues. We first use a state-of-art, deep scene semantic parsing method and a face attribute extractor to understand how different cues present in a scene relate to human perception of ambiance on Foursquare images of social venues. We then analyze correlational links between visual cues and thirteen ambiance variables, as well as the ability of the semantic attributes to automatically infer place ambiance. We study the effect of the type and amount of image data used for learning, and compare regression results to previous work, showing that the proposed approach results in marginal-to-moderate performance increase for up to ten of the ambiance dimensions, depending on the corpus.

This work introduces a wearable system to provide situational awareness for blind and visually impaired people. The system includes a camera, an embedded computer and a haptic device to provide feedback when an obstacle is detected. The system uses techniques from computer vision and motion planning to (1) identify walkable space; (2) plan step-by-step a safe motion trajectory in the space, and (3) recognize and locate certain types of objects, for example the location of an empty chair. These descriptions are communicated to the person wearing the device through vibrations. We present results from user studies with low- and high-level tasks, including walking through a maze without collisions, locating a chair, and walking through a crowded environment while avoiding people.

Objective Apolipoprotein E ( APOE ) genotype is a determinant of neurologic recovery after brain ischemia and traumatic brain injury. The APOE e2 allele has been associated with worse neurodevelopmental (ND) outcome after repair of congenital heart defects (CHD) in infancy. Replication of this finding in an independent cohort is essential to validate the observed genotype-phenotype association. Methods The association of APOE genotype with ND outcomes was assessed in a combined cohort of patients with single-ventricle CHD enrolled in the Single Ventricle Reconstruction and Infant Single Ventricle trials. ND outcome was assessed at 14 months using the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development-II. Stepwise multivariable regression was performed to develop predictive models for PDI and MDI scores. Results Complete data were available for 298 of 435 patients. After adjustment for preoperative and postoperative covariates, the APOE e2 allele was associated with a lower PDI score ( P = .038). Patients with the e2 allele had a PDI score approximately 6 points lower than those without the risk allele, explaining 1.04% of overall PDI variance, because the e2 allele was present in only 11% of the patients. There was a marginal effect of the e2 allele on MDI scores ( P = .058). Conclusions These data validate the association of the APOE e2 allele with adverse early ND outcomes after cardiac surgery in infants, independent of patient and operative factors. Genetic variants that decrease neuroresilience and impair neuronal repair after brain injury are important risk factors for ND dysfunction after surgery for CHD.

Mowat-Wilson syndrome (MWS) is characterized by moderate to severe intellectual disability and distinctive facial features in association with variable structural congenital anomalies/clinical features including congenital heart disease, Hirschsprung disease, hypospadias, agenesis of the corpus callosum, short stature, epilepsy, and microcephaly. Less common clinical features include ocular anomalies, craniosynostosis, mild intellectual disability, and choanal atresia. These cases may be more difficult to diagnose. In this report, we add 28 MWS patients with molecular confirmation of ZEB2 mutation, including seven with an uncommon presenting feature. Among the "unusual" patients, two patients had clinical features of charge syndrome including choanal atresia, coloboma, cardiac defects, genitourinary anomaly (1/2), and severe intellectual disability; two patients had craniosynostosis; and three patients had mild intellectual disability. Sixteen patients have previously-unreported mutations in ZEB2. Genotype-phenotype correlations were suggested in those with mild intellectual disability (two had a novel missense mutation in ZEB2, one with novel splice site mutation). This report increases the number of reported patients with MWS with unusual features, and is the first report of MWS in children previously thought to have CHARGE syndrome. These patients highlight the importance of facial gestalt in the accurate identification of MWS when less common features are present.

Because a tracheal cartilaginous sleeve (TCS) confers a significant mortality risk that can be mitigated with appropriate intervention, we sought to describe the prevalence and associated genotypes in a large cohort of children with syndromic craniosynostosis. Chart review of patients with syndromic craniosynostosis across two institutions. In a cohort of 86 patients with syndromic craniosynostosis, 31 required airway evaluation under anesthesia. TCS was found in 19, for an overall prevalence of 22%. FGFR2, TWIST1, and FGFR3 mutations were identified in children with TCS. All five children with a W290C mutation in FGFR2 had TCS, and most previously reported children with W290C had identification of TCS or early death. In contrast, TCS was not associated with other mutations at residue 290. There is an association between TCS and syndromic craniosynostosis, and it appears to be particularly high in individuals with the W290C mutation in FGFR2. Referral to a pediatric otolaryngologist and consideration of operative airway evaluation (i.e., bronchoscopy or rigid endoscopy) in all patients with syndromic craniosynostosis should be considered to evaluate for TCS. Results from genetic testing may help providers weigh the risks and benefits of early airway evaluation and intervention in children with higher-risk genotypes. Genet Med 19 1, 62–68.

Sea buckthorn (Hippophae rhamnoides L.) constitutes thorny nitrogen fixing deciduous shrub. Sea buckthorn(SBT) is primarily valued for its very rich vitamins A, B1, B12, C, E, K, and P; flavonoids, lycopene, carotenoids, and phytosterols. and therapeutically important since it is rich with potent antioxidants. Scientifically evaluated pharmacological actions of SBT are like inflammation inhibited by reduced permeability, loss of follicular aggregation of lymphocytes from the inflamed synovium and suppress lymphocyte proliferation. SBT-reduced recurrence of angina, ischemic electrocardiogram which might be due to decreased myocardial oxygen consumption and inhibition of platelet aggregation induced by collagen. SBT can kill both cancer cells of S180, P388, SGC7901 and lymphatic leukemia (L1200). The antiulcer activity may be related to reduce gastric empty time, inhibiting proteolytic activity and promoting wound reparation processes of mucosa. SBT exerts antihypertensive effect in part by blocking angiotensin-2 receptor on cell surface. SBT decreased the level of stress hormones and enhanced hypoxic tolerance in animals indicating its anti-stress, adaptogenic activity. A lot of research work is still needed to find cellular and molecular mechanisms of these activities and also yet to be explored for its activity in osteoporosis, hemorrhage, cataract, urinary stone, acne, psoriasis, polyneuritis, cheilosis, glossities, baldness, anti-obesity, gout, and chronic prostitis.

Compared with the echolocation performance of an expert who is blind, sighted novices rapidly learned size and position discrimination with surprising precision. We used a novel task to characterize the population distribution of echolocation skills in sighted persons and report the highest-known human echolocation acuity in the expert who is blind.

Objective: We present a device that combines principles of ultrasonic echolocation and spatial hearing to provide human users with environmental cues that are 1) not otherwise available to the human auditory system, and 2) richer in object and spatial information than the more heavily processed sonar cues of other assistive devices. The device consists of a wearable headset with an ultrasonic emitter and stereo microphones with affixed artificial pinnae. The goal of this study is to describe the device and evaluate the utility of the echoic information it provides. Methods: The echoes of ultrasonic pulses were recorded and time stretched to lower their frequencies into the human auditory range, then played back to the user. We tested performance among naive and experienced sighted volunteers using a set of localization experiments, in which the locations of echo-reflective surfaces were judged using these time-stretched echoes. Results: Naive subjects were able to make laterality and distance judgments, suggesting that the echoes provide innately useful information without prior training. Naive subjects were generally unable to make elevation judgments from recorded echoes. However, trained subjects demonstrated an ability to judge elevation as well. Conclusion: This suggests that the device can be used effectively to examine the environment and that the human auditory system can rapidly adapt to these artificial echolocation cues. Significance: Interpreting and interacting with the external world constitutes a major challenge for persons who are blind or visually impaired. This device has the potential to aid blind people in interacting with their environment.

Nairobi is one of the fastest growing metropolitan cities and a major business and technology powerhouse in Africa. However, Nairobi currently lacks monitoring technologies to obtain reliable data on traffic and road infrastructure conditions. In this paper, we investigate the use of mobile crowdsourcing as means to gather and document Nairobi's road quality information. We first present the key findings of a city-wide road quality survey about the perception of existing road quality conditions in Nairobi. Based on the survey's findings, we then developed a mobile crowdsourcing application, called CommuniSense, to collect road quality data. The application serves as a tool for users to locate, describe, and photograph road hazards. We tested our application through a two-week field study amongst 30 participants to document various forms of road hazards from different areas in Nairobi. To verify the authenticity of user-contributed reports from our field study, we proposed to use online crowdsourcing using Amazon's Mechanical Turk (MTurk) to verify whether submitted reports indeed depict road hazards. We found 92% of user-submitted reports to match the MTurkers judgements. While our prototype was designed and tested on a specific city, our methodology is applicable to other developing cities., Comment: In Proceedings of 17th International Conference on Human-Computer Interaction with Mobile Devices and Services (MobileHCI 2015)

The current study was undertaken to investigate the effect of the root bark of Oroxylum indicum. Vent. (Bignoniaceae) against experimental gastric ulcers. The 50% alcohol extract of root bark of Oroxylum indicum. and its different fractions, viz., petroleum ether, chloroform, ethyl acetate and n.-butanol, were studied (p.o.) against ethanol-induced gastric mucosal damage. The alcohol extract (300 mg/kg) and its different fractions (100 and 300 mg/kg) showed significant reduction in gastric ulceration. Out of all these fractions, the petroleum ether (96%) and n.-butanol (99%) fractions showed maximum inhibition of gastric lesions against ethanol-induced gastric mucosal damage. The results were comparable with omeprazole (reference standard). In the ethanol-induced gastric ulcer model, treatment with both the active fractions and omeprazole showed significant antioxidant activity as evident from the reduction in the extent of lipid peroxidation that was measured in terms of malondialdehyde (MDA), al...

The current study was designed to investigate the effect of a 50% alcohol extract of Chlorophytum arundinaceum. Baker (CAE) against ethanol-induced pylorus ligation and cold stress–induced experimental gastric ulcer. The CAE was given at the dose of 100 mg/kg, p.o., in all the models, and results of those were compared with that of animals treated with omeprazole 20 mg/kg, p.o. (reference standard). Ulcer index was a common evaluating parameter in all the models. In the pylorus ligation model, acid secretory parameters (total acid, pepsin activity, and total acid output) and mucoprotective parameters (total carbohydrate, total protein, and mucin activity) were studied. In addition, lipid peroxidation and antioxidant activity were specifically studied in cold stress–induced gastric ulcer model. Effects on vascular permeability as well as gastric emptying were also studied. CAE has shown significant protection in gastric ulceration as evident from reduction (p

The present study was designed to investigate the effect of Mimusops elengi (Sapotaceae) against experimental gastric ulcers. The 50% alcoholic extract of Mimusops elengi (Ext E) and its different fractions namely ethyl acetate (Ext E1), n-butanol (Ext E2), methanol (Ext E3) and aqueous (Ext E4) were studied (p.o.) against ethanol-induced gastric damage. Ext E1 was also studied in ethanol-induced, pylorus-ligated and water-immersion plus stress-induced gastric ulcer models. Ranitidine HCl (80 mg kg(-1)) was used as a reference standard. In ethanol-induced gastric ulcer model, pantoprazole (20 mg kg(-1)) was also used as a reference standard. Ext E1 tested in mice up to the dose of 5000 mg kg(-1) (p.o.) did not produce any sign of toxicity. Ext E at the doses of 50, 100, 300 and 500 mg kg(-1) and its different fractions (100 mg kg(-1)) showed reduction in gastric ulceration (P0.05). Ext E1 at the doses of 10, 50 and 100 mg kg(-1) showed dose-dependent inhibition of gastric lesions against ethanol-induced gastric damage. In 19 h pylorus-ligated animals, Ext E1 at 50 and 100 mg kg(-1) doses showed significant reduction in ulcer index (P0.05). Significant reduction was also observed in total acidity, volume of gastric acid secretion, total acid output and pepsin activity (P0.05) when compared with the control group. Besides, Ext E1 showed increase in the mucosal glycoproteins that was evident from significant rise in total carbohydrates to protein ratio (TC:PR ratio) (P0.05), which is an indication of mucin activity. Ext E1 also showed protection against water-immersion plus stress-induced gastric lesions that was evident from dose-dependent decrease in ulcer index (P0.05), score for intensity (P0.05) and total lesion area (P0.05) when compared with the control group. It can be concluded from our study that Ext E1 possesses anti-ulcer activity against experimental gastric ulcers. The mechanism of anti-ulcer activity can be attributed to decrease in gastric acid secretory activity along with strengthening of mucosal defensive mechanisms.

Objective:ATAD1 encodes Thorase, a mediator of α-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) receptor recycling; in this work, we characterized the phenotype resulting from ATAD1 mutations and developed a targeted therapy in both mice and humans.Methods:Using exome sequencing, we identified a novel ATAD1 mutation (p.E276X) as the etiology of a devastating neurologic disorder characterized by hypertonia, seizures, and death in a consanguineous family. We postulated that pathogenesis was a result of excessive AMPA receptor activity and designed a targeted therapeutic approach using perampanel, an AMPA-receptor antagonist.Results:Perampanel therapy in ATAD1 knockout mice reversed behavioral defects, normalized brain MRI abnormalities, prevented seizures, and prolonged survival. The ATAD1 patients treated with perampanel showed improvement in hypertonicity and resolution of seizures.Conclusions:This work demonstrates that identification of novel monogenic neurologic disorders and observation of response to targeted therapeutics can provide important insights into human nervous system functioning.

Revelations of the multifactorial pathogenesis of type 2 diabetes mellitus (T2DM) that extend beyond the role of insulin and glucose utilization have been crucial in redefining the treatment paradigm. The focus of treatment is currently directed towards achieving wide-ranging targets encompassing the management of cardiovascular comorbidities that have been evidenced as indispensable aspects of T2DM. While most currently prescribed antihyperglycemic agents have little or no effect on reducing cardiovascular risks, some have been associated with undesirable effects on common risk factors such as weight gain and cardiovascular sequelae. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are newer additions to the array of therapeutic agents for T2DM that have demonstrated robust glycemic control as mono and add-on therapies. Their unique renal mode of action, independent of insulin modulation, confers complementary metabolic benefits. By virtue of these effects, SGLT2i may have a distinct role in the revised treatment recommendations by established working groups such as the American Diabetes Association and the American Association of Clinical Endocrinologists that advocate a more comprehensive management of T2DM, not restricting to glycemic targets. The current review gives an overview of the changing treatment needs for T2DM and discusses the nonglycemic effects of SGLT2i. It provides an updated summary on the efficacy of canagliflozin, dapagliflozin, and empagliflozin in promoting weight loss, stabilizing blood pressure, and other favorable metabolic effects.

In this poster, we present a mobile crowdsourcing application, called Afya Ya Barabara (AYB) (which means road health in Kiswahili). The application serves 2 major roles: First is to collect and visualize data on road surface conditions in Nairobi. Second role is as a citizen engagement platform to raise awareness on the state of road conditions in Nairobi using Twitter hashtags. The focus of this work is to discuss how AYB is employed to promote citizen engagement. Nairobi is one of the most active cities in East Africa in terms of Twitter usage. This guided our decision to employ Twitter as a social engagement tool. The demand for more systematic citizen engagement and public participation in the governance of developing cities is growing. As government budgets are becoming increasingly tight, new ways of addressing road maintenance problems are required. Public governance in developing countries faces accountability issues that allow corruption and poor service delivery to seethe. Lack of information and citizen engagement perpetuates such tendencies. We propose Afya Ya Barabara as an engagement platform that will expand the capacity of municipalities and its citizens to better monitor road conditions using mobile technology.

New research cutting across architecture, urban studies, and psychology is contextualizing the understanding of urban spaces according to the perceptions of their inhabitants. One fundamental construct that relates place and experience is ambiance, which is defined as "the mood or feeling associated with a particular place". We posit that the systematic study of ambiance dimensions in cities is a new domain for which multimedia research can make pivotal contributions. We present a study to examine how images collected from social media can be used for the crowdsourced characterization of indoor ambiance impressions in popular urban places. We design a crowdsourcing framework to understand suitability of social images as data source to convey place ambiance, to examine what type of images are most suitable to describe ambiance, and to assess how people perceive places socially from the perspective of ambiance along 13 dimensions. Our study is based on 50,000 Foursquare images collected from 300 popular places across six cities worldwide. The results show that reliable estimates of ambiance can be obtained for several of the dimensions. Furthermore, we found that most aggregate impressions of ambiance are similar across popular places in all studied cities. We conclude by presenting a multidisciplinary research agenda for future research in this domain. © 2015 ACM.

The present study was designed to evaluate the effects of a potassium channel opener, nicorandil, and to elucidate its possible mechanism of action in aspirin plus pylorus ligation induced and ethanol-induced gastric ulcers in rats. In an attempt to ascertain the involvement of KATP channels in the modulation of gastric ulcers, the effects of nicorandil alone as well as in the presence of the KATP channel blocker glibenclamide were studied. Nicorandil and glibenclamide were administered orally at a dose of 2 mg/kg throughout the study. Nicorandil showed significant protection in all the selected models that was evident from a significant reduction in the ulcer index. The results of nicorandil treatment were comparable with those of cimetidine treatment in both models. Glibenclamide was found to inhibit this effect of nicorandil. Further, glibenclamide showed proulcerogenic potential in ethanol and aspirin plus pylorus ligation models. In the aspirin plus pylorus ligation model, nicorandil showed a significant reduction in total acidity, pepsin activity, and protein content and a significant rise in mucin activity. The effect of nicorandil was also studied on gastric mucosal blood flow (GMBF). The GMBF was found to be more increased in the test group than in the control group, indicating enhancement of GMBF by nicorandil. Glibenclamide reversed this effect of nicorandil as well. It is concluded from our study that nicorandil possesses antiulcer activity in the models employed in the present study. This may be attributed to the opening of KATP channels, inhibition of acid secretion, enhancement of mucin activity, and improvement in GMBF.