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Breast parenchymal patterns on radiologic images are associated with breast cancer risk. Radiomic features have been proposed as quantitative measures of parenchymal patterns. We defined intrinsic imaging phenotypes of breast parenchymal patterns based on radiomic features extracted from full field digital mammography (FFDM) in breast screening populations and assessed whether these phenotypes are associated with breast cancer risk and masking. We selected 30,000 women with 4-view FFDM exams from Hologic machines from three institutions (Hospital of the University of Pennsylvania, Mayo Clinic, and San Francisco Mammography Registry), randomly split into a training (20,000 women) and test set (10,000 women). In total, 390 radiomic features were automatically extracted from each image using a validated software pipeline, standardized, and adjusted for site differences using ComBat. We used two methods, hierarchical clustering and Principal Components (PCs) analysis, to classify significant variation among the features in the training set and replicate among the test set. Next, we applied the replicated clusters and PCs to an independent nested case-control set [1082 invasive breast cancer (BC) cases (of which 151 were Black and 893 White women, 38 other race) matched to 2837 controls (411 Black and 2345 White women, 81 other race) on age, race, timing of images, and site]. We examined associations of the clusters and PCs with invasive breast cancer risk, as well as masking [defined as a false-negative (FN) screen (124 cases and 319 matched controls) and additionally the subset with symptomatic interval cancer (IC) within 12 months of negative screen (88 cases and 223 matched controls)] using conditional logistic regression. We evaluated their association with breast cancer alone, and with adjustment for age, body mass index (BMI) and breast density assessed by Breast Imaging Reporting and Data System (BI-RADS) using likelihood ratio tests. We estimated discrimination using area under the curve (AUC) and compared AUCs for models that included the radiomic clusters and PCs with the model that included only age, BMI and density. We also stratified analyses by race (Black/White). From hierarchical clustering, we defined six statistically significant phenotype clusters (each of at least 1000 women) in the training set which were replicated in the test set. For PC Analysis, we identified six PCs in the training set, explaining 85% of the variation in texture features and reproduced these in the test set. The six radiomic phenotype clusters (P< 0.001) and six PCs (P< 0.001) were both associated with invasive BC, including after adjusting for age, BMI, and density (cluster P=0.004; PCs P< 0.001). Improvements in discrimination of invasive BC with inclusion of PCs or clusters were more pronounced among Black women (Table). Further, the PCs (P< 0.001) and clusters (P< 0.001) were significantly associated with FN overall and for symptomatic IC (PCs P< 0.001; clusters P=0.001), but only PCs remained significant after adjusting for age, BMI and density (PCs P=0.004 for FN; PCs P=0.007 for symptomatic IC). Discrimination of masking also improved with inclusion of both clusters and PCs (Table). We identified reproducible radiomic phenotypes that are associated with invasive BC risk, above and beyond breast density with the strongest associations for invasive BC among Black women and symptomatic interval cancers. Citation Format: Stacey Winham, Anne Marie McCarthy, Aimilia Gastounioti, Christopher Scott, Aaron Norman, Walter C. Mankowski, Lauren Pantalone, Matthew Jensen, Eric A. Cohen, Hannah Horng, Kathleen Brandt, Emily F. Conant, Karla Kerlikowske, Despina Kontos, Celine Vachon. Radiomic phenotypes of breast texture and association with breast cancer risk and masking [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-06.

Objective Suction-assisted laryngoscopy and airway decontamination (SALAD) was created to assist with the decontamination of a massively soiled airway. This study aims to investigate the usefulness of SALAD training to prehospital emergency providers to improve their ability to intubate a massively contaminated airway. Methods This was a prospective study conducted as a before and after teaching intervention. Participants were made up of prehospital providers who were present at regularly scheduled training sessions and were asked to intubate a high-fidelity mannequin simulating large-volume emesis before and after SALAD instruction. They were subsequently tested on 3-month skill retention. Twenty subjects participated in all stages of the study and were included in the analysis. Results The median time to successful intubation for all study participants before instruction was 60.5 seconds (interquartile range [IQR] = 44.0-84.0); post-training was 43.0 seconds (IQR = 38.0-57.5); and at the 3-month follow-up, it was 29.5 seconds (IQR = 24.5-39.0). The greatest improvement was seen on subgroup analysis of the slowest 50th percentile where the median time before instruction was 84.0 seconds (IQR = 68.0-96.0); post-instruction was 41.5 seconds (IQR = 36.0-65.0); and at the 3-month follow-up, it was 29.5 seconds (IQR = 25.0-39.0). Conclusion The implementation of the SALAD technique through a structured educational intervention improved time to intubation and the total number of attempts.

The Enterobacteriales order is composed of Gram-negative bacteria that range from harmless symbionts to well-studied pathogens. We announce complete genome sequences of five related SO-1-like Enterobacteriales bacteriophages (also known as the Dhillonvirus genus) isolated from wastewater that infect Escherichia coli (Opt-212, Over9000, Pubbukkers, and Teewinot) or Shigella boydii (StarDew).

The

There have been many tactics throughout the years aimed at reducing central line-associated bloodstream infections (CLABSI) in the healthcare setting. To reduce CLABSI rates at this facility, we employed cognitive science-based online training directed at nursing departments. Following implementation, we found significant reductions in CLABSI rates that were sustained for a minimum of 9 months. These results demonstrate that this learning methodology can be used to help decrease CLABSI and potentially other health care-associated infections.

Background Breast terminal duct lobular units (TDLUs), the source of most breast cancer (BC) precursors, are shaped by age-related involution, a gradual process, and postpartum involution (PPI), a dramatic inflammatory process that restores baseline microanatomy after weaning. Dysregulated PPI is implicated in the pathogenesis of postpartum BCs. We propose that assessment of TDLUs in the postpartum period may have value in risk estimation, but characteristics of these tissues in relation to epidemiological factors are incompletely described. Methods Using validated Artificial Intelligence and morphometric methods, we analyzed digitized images of tissue sections of normal breast tissues stained with hematoxylin and eosin from donors ≤ 45 years from the Komen Tissue Bank (180 parous and 545 nulliparous). Metrics assessed by AI, included: TDLU count; adipose tissue fraction; mean acini count/TDLU; mean dilated acini; mean average acini area; mean “capillary” area; mean epithelial area; mean ratio of epithelial area versus intralobular stroma; mean mononuclear cell count (surrogate of immune cells); mean fat area proximate to TDLUs and TDLU area. We compared epidemiologic characteristics collected via questionnaire by parity status and race, using a Wilcoxon rank sum test or Fisher’s exact test. Histologic features were compared between nulliparous and parous women (overall and by time between last birth and donation [recent birth: ≤ 5 years versus remote birth: > 5 years]) using multivariable regression models. Results Normal breast tissues of parous women contained significantly higher TDLU counts and acini counts, more frequent dilated acini, higher mononuclear cell counts in TDLUs and smaller acini area per TDLU than nulliparas (all multivariable analyses p 5 years postpartum, whereas increases in immune cells were most marked ≤ 5 years of a birth. Relationships were suggestively modified by several other factors, including demographic and reproductive characteristics, ethanol consumption and breastfeeding duration. Conclusions Our study identified sustained expansion of TDLU numbers and reduced average acini area among parous versus nulliparous women and notable increases in immune responses within five years following childbirth. Further, we show that quantitative characteristics of normal breast samples vary with demographic features and BC risk factors.

ObjectiveDescribe a case of NMDAR encephalitis in a young Latino male patient, additionally the factors resulting in delayed preventative and diagnostic medical care, which contributed to the development of a preventable case of NMDAR encephalitis.BackgroundAdolescent undocumented immigrants in the United States face a history of prejudice and bias that perpetuates disparities and stigmas related to their healthcare. The lack of culturally informed practices among healthcare workers can create multiple lost opportunities to deliver standard of care practices, including routine testicular exams. The treatment of NMDAR encephalitis with immunotherapy, and resection of culpable tumors when present, can be lifesaving. Recognition of the germ cell tumor association has also renewed awareness of the importance of screening for such tumors.Design/MethodsN/A.ResultsCase: A 25-year-old male who immigrated from Mexico to the U.S. at age 13 presented to the hospital for concern of status epilepticus. His past medical history included atypical developmental delay beginning in late teenage years. A large abdominal mass was identified on imaging as a stage IIIC (pT1bN0M1bS2) NSGCT (70% teratoma/30% seminoma) tumor arising from an unresected, undescended left testicle. Autonomic instability in the setting of this malignancy prompted an evaluation for, and diagnosis of, NMDAR encephalitis. His course was complicated by altered mental status, seizures, sympathetic storming, and orofacial dystonia. After tumor resection, and initiation of immune therapy, the patient showed a remarkable recovery.ConclusionsThis patient's preventive healthcare was impacted at multiple timepoints by changing political policies and a lack of culturally informed practices that unpredictably disrupted reliable access to medical care. Recognition of care gaps allows us to expand our differential diagnoses, and enact a comprehensive approach to fill in gaps. Effective communication, incorporating focused discussions within culturally sensitive frameworks, requires ongoing education for clinicians regarding the populations they serve to prevent disease and minimize health care disparities.

Copy number variants (CNVs) are a major cause of several genetic disorders, making their detection an essential component of genetic analysis pipelines. Current methods for detecting CNVs from exome-sequencing data are limited by high false-positive rates and low concordance because of inherent biases of individual algorithms. To overcome these issues, calls generated by two or more algorithms are often intersected using Venn diagram approaches to identify “high-confidence” CNVs. However, this approach is inadequate, because it misses potentially true calls that do not have consensus from multiple callers. Here, we present CN-Learn, a machine-learning framework that integrates calls from multiple CNV detection algorithms and learns to accurately identify true CNVs using caller-specific and genomic features from a small subset of validated CNVs. Using CNVs predicted by four exome-based CNV callers (CANOES, CODEX, XHMM, and CLAMMS) from 503 samples, we demonstrate that CN-Learn identifies true CNVs at higher precision (∼90%) and recall (∼85%) rates while maintaining robust performance even when trained with minimal data (∼30 samples). CN-Learn recovers twice as many CNVs compared to individual callers or Venn diagram–based approaches, with features such as exome capture probe count, caller concordance, and GC content providing the most discriminatory power. In fact, ∼58% of all true CNVs recovered by CN-Learn were either singletons or calls that lacked support from at least one caller. Our study underscores the limitations of current approaches for CNV identification and provides an effective method that yields high-quality CNVs for application in clinical diagnostics.

Traumatic spinal cord injuries are significant contributors to the morbidity and mortality burden of trauma patients worldwide, and consume significant resources in both their acute and rehabilitative care. Another cause of mortality and morbidity is hypertrophic obstructive cardiomyopathy, which can cause syncope or sudden cardiac death in patients with no known prior cardiac disease. This case report describes a unique combination of these two high-risk pathologies in a scene trauma patient, and provides an overview of the pathophysiology and treatment of these high-risk disease processes.

Spaceflight poses risks to the central nervous system (CNS), and understanding neurological responses is important for future missions. We report CNS changes in Drosophila aboard the International Space Station in response to spaceflight microgravity (SFμg) and artificially simulated Earth gravity (SF1g) via inflight centrifugation as a countermeasure. While inflight behavioral analyses of SFμg exhibit increased activity, postflight analysis displays significant climbing defects, highlighting the sensitivity of behavior to altered gravity. Multi-omics analysis shows alterations in metabolic, oxidative stress and synaptic transmission pathways in both SFμg and SF1g; however, neurological changes immediately postflight, including neuronal loss, glial cell count alterations, oxidative damage, and apoptosis, are seen only in SFμg. Additionally, progressive neuronal loss and a glial phenotype in SF1g and SFμg brains, with pronounced phenotypes in SFμg, are seen upon acclimation to Earth conditions. Overall, our results indicate that artificial gravity partially protects the CNS from the adverse effects of spaceflight.

Background Recent studies have suggested that individual variants do not sufficiently explain the variable expressivity of phenotypes observed in complex disorders. For example, the 16p12.1 deletion is associated with developmental delay and neuropsychiatric features in affected individuals, but is inherited in > 90% of cases from a mildly-affected parent. While children with the deletion are more likely to carry additional “second-hit” variants than their parents, the mechanisms for how these variants contribute to phenotypic variability are unknown. Methods We performed detailed clinical assessments, whole-genome sequencing, and RNA sequencing of lymphoblastoid cell lines for 32 individuals in five large families with multiple members carrying the 16p12.1 deletion. We identified contributions of the 16p12.1 deletion and “second-hit” variants towards a range of expression changes in deletion carriers and their family members, including differential expression, outlier expression, alternative splicing, allele-specific expression, and expression quantitative trait loci analyses. Results We found that the deletion dysregulates multiple autism and brain development genes such as FOXP1, ANK3, and MEF2. Carrier children also showed an average of 5323 gene expression changes compared with one or both parents, which matched with 33/39 observed developmental phenotypes. We identified significant enrichments for 13/25 classes of “second-hit” variants in genes with expression changes, where 4/25 variant classes were only enriched when inherited from the noncarrier parent, including loss-of-function SNVs and large duplications. In 11 instances, including for ZEB2 and SYNJ1, gene expression was synergistically altered by both the deletion and inherited “second-hits” in carrier children. Finally, brain-specific interaction network analysis showed strong connectivity between genes carrying “second-hits” and genes with transcriptome alterations in deletion carriers. Conclusions Our results suggest a potential mechanism for how “second-hit” variants modulate expressivity of complex disorders such as the 16p12.1 deletion through transcriptomic perturbation of gene networks important for early development. Our work further shows that family-based assessments of transcriptome data are highly relevant towards understanding the genetic mechanisms associated with complex disorders.

A neurodevelopmental disorder-associated gene, ISWI/SMARCA5, acts during development to coordinate sleep later in life., Sleep disruptions are among the most commonly reported symptoms across neurodevelopmental disorders (NDDs), but mechanisms linking brain development to normal sleep are largely unknown. From a Drosophila screen of human NDD-associated risk genes, we identified the chromatin remodeler Imitation SWItch/SNF (ISWI) to be required for adult fly sleep. Loss of ISWI also results in disrupted circadian rhythms, memory, and social behavior, but ISWI acts in different cells and during distinct developmental times to affect each of these adult behaviors. Specifically, ISWI expression in type I neuroblasts is required for both adult sleep and formation of a learning-associated brain region. Expression in flies of the human ISWI homologs SMARCA1 and SMARCA5 differentially rescues adult phenotypes, while de novo SMARCA5 patient variants fail to rescue sleep. We propose that sleep deficits are a primary phenotype of early developmental origin in NDDs and point toward chromatin remodeling machinery as critical for sleep circuit formation.

With more than a quarter of the population of the United States of America living greater than 60 minutes from the nearest level I or II trauma center, the utilization of helicopter emergency medical services provides a lifeline for the critically ill and injured. The use of prehospital ultrasound in the HEMS environment can provide improved diagnostic accuracy, accelerate a patient’s care timeline, guide therapy and procedures, and assist crew decision-making. These myriads of benefits, however, come at the potential cost of space limitations within the aircraft, training burdens for initial and refresher competencies, the need for physician-based QA/QI, and the cost of introducing such a program. Each aeromedical transport program needs to weigh the perceived advantages and challenges of utilizing prehospital ultrasound and make an informed decision as to whether its use would benefit the patient population they serve.

We previously identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental outcomes, where severely affected probands carried an excess of rare pathogenic variants compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, while “second-hits” in the genetic background modulate the phenotypic trajectory. To test this model, we examined how neurodevelopmental defects conferred by knockdown of individual 16p12.1 homologs are modulated by simultaneous knockdown of homologs of “second-hit” genes inDrosophila melanogasterandXenopus laevis. We observed that knockdown of 16p12.1 homologs affect multiple phenotypic domains, leading to delayed developmental timing, seizure susceptibility, brain alterations, abnormal dendrite and axonal morphology, and cellular proliferation defects. Compared to genes within the 16p11.2 deletion, which has higherde novooccurrence, 16p12.1 homologs were less likely to interact with each other inDrosophilamodels or a human brain-specific interaction network, suggesting that interactions with “second-hit” genes may confer higher impact towards neurodevelopmental phenotypes. Assessment of 212 pairwise interactions inDrosophilabetween 16p12.1 homologs and 76 homologs of patient-specific “second-hit” genes (such asARID1BandCACNA1A), genes within neurodevelopmental pathways (such asPTENandUBE3A), and transcriptomic targets (such asDSCAMandTRRAP) identified genetic interactions in 63% of the tested pairs. In 11 out of 15 families, homologs of patient-specific “second-hits” enhanced or suppressed the phenotypic effects of one or many 16p12.1 homologs. In fact, homologs ofSETD5synergistically interacted with homologs ofMOSMOin bothDrosophilaandX. laevis, leading to modified cellular and brain phenotypes, as well as axon outgrowth defects that were not observed with knockdown of either individual homolog. Our results suggest that several 16p12.1 genes sensitize the genome towards neurodevelopmental defects, and complex interactions with “second-hit” genes determine the ultimate phenotypic manifestation.Author SummaryCopy-number variants, or deletions and duplications in the genome, are associated with multiple neurodevelopmental disorders. The developmental delay-associated 16p12.1 deletion is mostly inherited, and severely affected children carry an excess of “second-hits” variants compared to mildly affected carrier parents, suggesting that additional variants modulate the clinical manifestation. We studied this “two-hit” model usingDrosophilaandXenopus laevis, and systematically tested how homologs of “second-hit” genes modulate neurodevelopmental defects observed for 16p12.1 homologs. We observed that 16p12.1 homologs independently led to multiple neurodevelopmental features and weakly interacted with each other, suggesting that interactions with “second-hit” homologs potentially have a higher impact towards neurodevelopmental defects than interactions between 16p12.1 homologs. We tested 212 pairwise interactions of 16p12.1 homologs with “second-hit” homologs and genes within conserved neurodevelopmental pathways, and observed modulation of neurodevelopmental defects caused by 16p12.1 homologs in 11 out of 15 families, and 16/32 of these changes could be attributed to genetic interactions. Interestingly, we observed thatSETD5homologs interacted with homologs ofMOSMO, which conferred additional neuronal phenotypes not observed with knockdown of individual homologs. We propose that the 16p12.1 deletion sensitizes the genome to multiple neurodevelopmental defects, and complex interactions with “second-hit” genes determine the clinical trajectory of the disorder.

Sleep disruptions are among the most commonly-reported symptoms across neurodevelopmental disorders (NDDs), but mechanisms linking brain development to normal sleep are largely unknown. From aDrosophilascreen of human NDD-associated risk genes, we identified the chromatin remodelerImitation SWItch/SNF(ISWI) to be required for adult fly sleep. Loss ofISWIalso results in disrupted circadian rhythms, memory, and social behavior, butISWIacts in different cells and during distinct developmental times to affect each of these adult behaviors. Specifically,ISWIexpression in type I neuroblasts is required for both adult sleep and formation of a learning-associated brain region. Expression in flies of the humanISWIhomologsSMARCA1andSMARCA5differentially rescue adult phenotypes. We propose that sleep deficits are a primary phenotype of early developmental origin in NDDs, and point towards chromatin remodeling machinery as critical for sleep circuit formation.

Rural beneficiaries make up nearly one quarter of the Medicare population, yet rural providers and patients face specific challenges with health and health care delivery that remain inadequately understood. Health disparities between rural and urban residents are widespread, barriers to health care in rural communities persist, and the rural health care workforce is limited. To better understand and track the relationship between rurality and performance under Medicare's payment programs, researchers must be able to identify rural beneficiaries, providers, and hospitals. Although numerous definitions of rurality are applied across the Medicare program, empirical research is lacking comparing the different definitions of rurality and the impact of their application to quality, outcome, or costs. Definitions that recognize rurality as a graded concept, rather than a dichotomous one, hold promise. Understanding the strengths and limitations of different approaches to identifying rurality will help researchers choose the best method for their particular purpose, and help policymakers interpret studies using these approaches.

The 1.6 Mbp deletion on chromosome 3q29 is associated with a range of neurodevelopmental disorders, including schizophrenia, autism, microcephaly, and intellectual disability. Despite its importance towards neurodevelopment, the role of individual genes, genetic interactions, and disrupted biological mechanisms underlying the deletion have not been thoroughly characterized. Here, we used quantitative methods to assay Drosophila melanogaster and Xenopus laevis models with tissue-specific individual and pairwise knockdown of 14 homologs of genes within the 3q29 region. We identified developmental, cellular, and neuronal phenotypes for multiple homologs of 3q29 genes, potentially due to altered apoptosis and cell cycle mechanisms during development. Using the fly eye, we screened for 314 pairwise knockdowns of homologs of 3q29 genes and identified 44 interactions between pairs of homologs and 34 interactions with other neurodevelopmental genes. Interestingly, NCBP2 homologs in Drosophila (Cbp20) and X. laevis (ncbp2) enhanced the phenotypes of homologs of the other 3q29 genes, leading to significant increases in apoptosis that disrupted cellular organization and brain morphology. These cellular and neuronal defects were rescued with overexpression of the apoptosis inhibitors Diap1 and xiap in both models, suggesting that apoptosis is one of several potential biological mechanisms disrupted by the deletion. NCBP2 was also highly connected to other 3q29 genes in a human brain-specific interaction network, providing support for the relevance of our results towards the human deletion. Overall, our study suggests that NCBP2-mediated genetic interactions within the 3q29 region disrupt apoptosis and cell cycle mechanisms during development., Author summary Rare copy-number variants, or large deletions and duplications in the genome, are associated with a wide range of neurodevelopmental disorders. The 3q29 deletion confers an increased risk for schizophrenia and autism. To understand the conserved biological mechanisms that are disrupted by this deletion, we systematically tested 14 individual homologs and 314 pairwise interactions of 3q29 genes for neuronal, cellular, and developmental phenotypes in Drosophila melanogaster and Xenopus laevis models. We found that multiple homologs of genes within the deletion region contribute towards developmental defects, such as larval lethality and disrupted cellular organization. Interestingly, we found that NCBP2 acts as a key modifier gene within the region, enhancing the developmental phenotypes of each of the homologs for other 3q29 genes and leading to disruptions in apoptosis and cell cycle pathways. Our results suggest that multiple genes within the 3q29 region interact with each other through shared mechanisms and jointly contribute to neurodevelopmental defects.

Autism typically presents with a highly heterogeneous set of features, including frequent comorbidity with intellectual disability (ID). The overlap between these two phenotypes has confounded the accurate diagnosis and discovery of genetic factors associated with autism. We analyzed genetic variants in 2,290 individuals with autism from the Simons Simplex Collection (SSC) who have either ID or normal cognitive function to determine whether genes associated with autism also contribute towards ID comorbidity. We found that individuals who carried variants in a set of 173 reported autism-associated genes showed decreased IQ (p=5.49×10−6) and increased autism severity (p=0.013) compared with individuals without such variants. A subset of autism-associated genes also showed strong evidence for ID comorbidity in published case reports. We also found that individuals with high-functioning autism (IQ>100) had lower frequencies of CNVs (p=0.065) and LGD variants (p=0.021) compared with individuals who manifested both autism and ID (IQde novo LGD variants conferred a 1.53-fold higher risk (p=0.035) towards comorbid ID, while LGD mutations specifically disrupting autism-associated genes conferred a 4.85-fold increased risk (p=0.011) for comorbid ID. Furthermore, de novo LGD variants in individuals with high-functioning autism were more likely to disrupt genes with little functional relevance towards neurodevelopment, as demonstrated by evidence from pathogenicity metrics, expression patterns in the developing brain, and mouse model phenotypes. Overall, our data suggest that de novo pathogenic variants disrupting genes associated with autism contribute towards autism and ID comorbidity, while other genetic factors are likely to be causal for high-functioning autism.

BackgroundNeurodevelopmental disorders (NDDs) such as autism spectrum disorder, intellectual disability, developmental disability, and epilepsy are characterized by abnormal brain development that may affect cognition, learning, behavior, and motor skills. High co-occurrence (comorbidity) of NDDs indicates a shared, underlying biological mechanism. The genetic heterogeneity and overlap observed in NDDs make it difficult to identify the genetic causes of specific clinical symptoms, such as seizures.MethodsWe present a computational method, MAGI-S, to discover modules or groups of highly connected genes that together potentially perform a similar biological function. MAGI-S integrates protein-protein interaction and co-expression networks to form modules centered around the selection of a single “seed” gene, yielding modules consisting of genes that are highly co-expressed with the seed gene. We aim to dissect the epilepsy phenotype from a general NDD phenotype by providing MAGI-S with high confidence NDD seed genes with varying degrees of association with epilepsy, and we assess the enrichment of de novo mutation, NDD-associated genes, and relevant biological function of constructed modules.ResultsThe newly identified modules account for the increased rate of de novo non-synonymous mutations in autism, intellectual disability, developmental disability, and epilepsy, and enrichment of copy number variations (CNVs) in developmental disability. We also observed that modules seeded with genes strongly associated with epilepsy tend to have a higher association with epilepsy phenotypes than modules seeded at other neurodevelopmental disorder genes. Modules seeded with genes strongly associated with epilepsy (e.g.,SCN1A,GABRA1, andKCNB1) are significantly associated with synaptic transmission, long-term potentiation, and calcium signaling pathways. On the other hand, modules found with seed genes that are not associated or weakly associated with epilepsy are mostly involved with RNA regulation and chromatin remodeling.ConclusionsIn summary, our method identifies modules enriched with de novo non-synonymous mutations and can capture specific networks that underlie the epilepsy phenotype and display distinct enrichment in relevant biological processes. MAGI-S is available athttps://github.com/jchow32/magi-s.

The 1.6 Mbp deletion on chromosome 3q29 is associated with a range of neurodevelopmental disorders, including schizophrenia, autism, microcephaly, and intellectual disability. Despite its importance towards neurodevelopment, the role of individual genes, genetic interactions, and disrupted biological mechanisms underlying the deletion have not been thoroughly characterized. Here, we used quantitative methods to assayDrosophila melanogasterandXenopus laevismodels with tissue-specific individual and pairwise knockdown of 14 homologs of genes within the 3q29 region. We identified developmental, cellular, and neuronal phenotypes for multiple homologs of 3q29 genes, potentially due to altered apoptosis and cell cycle mechanisms during development. Using the fly eye, we screened for 314 pairwise knockdowns of homologs of 3q29 genes and identified 44 interactions between pairs of homologs and 34 interactions with other neurodevelopmental genes. Interestingly,NCBP2homologs inDrosophila(Cbp20) andX. laevis(ncbp2) enhanced the phenotypes of homologs of the other 3q29 genes, leading to significant increases in apoptosis that disrupted cellular organization and brain morphology. These cellular and neuronal defects were rescued with overexpression of the apoptosis inhibitorsDiap1andxiapin both models, suggesting that apoptosis is one of several potential biological mechanisms disrupted by the deletion.NCBP2was also highly connected to other 3q29 genes in a human brain-specific interaction network, providing support for the relevance of our results towards the human deletion. Overall, our study suggests thatNCBP2-mediated genetic interactions within the 3q29 region disrupt apoptosis and cell cycle mechanisms during development.AUTHOR SUMMARYRare copy-number variants, or large deletions and duplications in the genome, are associated with a wide range of neurodevelopmental disorders. The 3q29 deletion confers an increased risk for schizophrenia, autism, and microcephaly. To understand the conserved biological mechanisms that are disrupted by this deletion, we systematically tested 14 individual homologs and 314 pairwise interactions of 3q29 genes for neuronal, cellular, and developmental phenotypes inDrosophila melanogasterandXenopus laevismodels. We found that multiple homologs of genes within the deletion region contribute towards developmental defects, such as larval lethality and disrupted cellular organization. Interestingly, we found thatNCBP2acts as a key modifier gene within the region, enhancing the developmental phenotypes of each of the homologs for other 3q29 genes and leading to disruptions in apoptosis and cell cycle pathways. Our results suggest that multiple genes within the 3q29 region interact with each other through shared mechanisms and jointly contribute to neurodevelopmental defects.

We previously identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental outcomes, where severely affected probands carried an excess of rare pathogenic variants compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, while “second-hits” in the genetic background modulate the phenotypic trajectory. To test this model, we examined how neurodevelopmental defects conferred by knockdown of individual 16p12.1 homologs are modulated by simultaneous knockdown of homologs of “second-hit” genes in Drosophila melanogaster and Xenopus laevis. We observed that knockdown of 16p12.1 homologs affect multiple phenotypic domains, leading to delayed developmental timing, seizure susceptibility, brain alterations, abnormal dendrite and axonal morphology, and cellular proliferation defects. Compared to genes within the 16p11.2 deletion, which has higher de novo occurrence, 16p12.1 homologs were less likely to interact with each other in Drosophila models or a human brain-specific interaction network, suggesting that interactions with “second-hit” genes may confer higher impact towards neurodevelopmental phenotypes. Assessment of 212 pairwise interactions in Drosophila between 16p12.1 homologs and 76 homologs of patient-specific “second-hit” genes (such as ARID1B and CACNA1A), genes within neurodevelopmental pathways (such as PTEN and UBE3A), and transcriptomic targets (such as DSCAM and TRRAP) identified genetic interactions in 63% of the tested pairs. In 11 out of 15 families, patient-specific “second-hits” enhanced or suppressed the phenotypic effects of one or many 16p12.1 homologs in 32/96 pairwise combinations tested. In fact, homologs of SETD5 synergistically interacted with homologs of MOSMO in both Drosophila and X. laevis, leading to modified cellular and brain phenotypes, as well as axon outgrowth defects that were not observed with knockdown of either individual homolog. Our results suggest that several 16p12.1 genes sensitize the genome towards neurodevelopmental defects, and complex interactions with “second-hit” genes determine the ultimate phenotypic manifestation., Author summary Copy-number variants, or deletions and duplications in the genome, are associated with multiple neurodevelopmental disorders. The developmental delay-associated 16p12.1 deletion is mostly inherited, and severely affected children carry an excess of “second-hits” variants compared to mildly affected carrier parents, suggesting that additional variants modulate the clinical manifestation. We studied this “two-hit” model using Drosophila and Xenopus laevis, and systematically tested how homologs of “second-hit” genes modulate neurodevelopmental defects observed for 16p12.1 homologs. We observed that 16p12.1 homologs independently led to multiple neurodevelopmental features and weakly interacted with each other, suggesting that interactions with “second-hit” homologs potentially have a higher impact towards neurodevelopmental defects than interactions between 16p12.1 homologs. We tested 212 pairwise interactions of 16p12.1 homologs with “second-hit” homologs and genes within conserved neurodevelopmental pathways, and observed modulation of neurodevelopmental defects caused by 16p12.1 homologs in 11 out of 15 families, and 16/32 of these changes could be attributed to genetic interactions. Interestingly, we observed that SETD5 homologs interacted with homologs of MOSMO, which conferred additional neuronal phenotypes not observed with knockdown of individual homologs. We propose that the 16p12.1 deletion sensitizes the genome to multiple neurodevelopmental defects, and complex interactions with “second-hit” genes determine the clinical trajectory of the disorder.

Medical error is the third-leading cause of death in the United States, just behind heart disease and cancer. We describe a software platform used to train healthcare workers to prevent their errors. The platform (Amplifire) harnesses artificial intelligence and principles of cognitive psychology. Amplifire’s AI continuously decides whether and when to require additional learning events, provide corrective and metacognitive feedback, and/or deliver self-regulatory guidance for the learner (e.g., “slow down”). Amplifire was deployed to several thousand nurses at a large healthcare system in attempts to reduce the rate of two types of hospital-acquired infections. The result was a 48% reduction in central-line-associated bloodstream infections (CLABSI) and a 32% reduction in catheter-associated urinary-tract infections (CAUTI). These findings demonstrate the effectiveness of using cognitive science along with AI in an e-learning platform.

Copy-number variants (CNVs) are a major cause of several genetic disorders, making their detection an essential component of genetic analysis pipelines. Current methods for detecting CNVs from exome sequencing data are limited by high false positive rates and low concordance due to the inherent biases of individual algorithms. To overcome these issues, calls generated by two or more algorithms are often intersected using Venn-diagram approaches to identify “high-confidence” CNVs. However, this approach is inadequate, as it misses potentially true calls that do not have consensus from multiple callers. Here, we present CN-Learn, a machine-learning framework (https://github.com/girirajanlab/CN_Learn) that integrates calls from multiple CNV detection algorithms and learns to accurately identify true CNVs using caller-specific and genomic features from a small subset of validated CNVs. Using CNVs predicted by four exome-based CNV callers (CANOES, CODEX, XHMM and CLAMMS) from 503 samples, we demonstrate that CN-Learn identifies true CNVs at higher precision (~90%) and recall (~85%) rates while maintaining robust performance even when trained with minimal data (~30 samples). CN-Learn recovers twice as many CNVs compared to individual callers or Venn diagram-based approaches, with features such as exome capture probe count, caller concordance and GC content providing the most discriminatory power. In fact, about 58% of all true CNVs recovered by CN-Learn were either singletons or calls that lacked support from at least one caller. Our study underscores the limitations of current approaches for CNV identification and provides an effective method that yields high-quality CNVs for application in clinical diagnostics.

Disparities by economic status are observed in the health status and health outcomes of Medicare beneficiaries. For health services and health policy researchers, one barrier to addressing these disparities is the ability to use Medicare data to ascertain information about an individual's income level or poverty, because Medicare administrative data contains limited information about individual economic status. Information gleaned from other sources-such as the Medicaid and Supplemental Security Income programs-can be used in some cases to approximate the income of Medicare beneficiaries. However, such information is limited in its availability and applicability to all beneficiaries. Neighborhood-level measures of income can be used to infer individual-level income, but level of neighborhood aggregation impacts accuracy and usability of the data. Community-level composite measures of economic status have been shown to be associated with health and health outcomes of Medicare beneficiaries and may capture neighborhood effects that are separate from individual effects, but are not readily available in Medicare data and do not serve to replace information about individual economic status. There is no single best method of obtaining income data from Medicare files, but understanding strengths and limitations of different approaches to identifying economic status will help researchers choose the best method for their particular purpose, and help policymakers interpret studies using measures of income.

Rare CNVs such as the 16p11.2 deletion are associated with extensive phenotypic heterogeneity, complicating disease gene discovery and functional evaluation. We used RNA interference in Drosophila melanogaster to evaluate the phenotype, function, and interactions of conserved 16p11.2 homologs in a tissue-specific manner. Using a series of quantitative methods for assessing developmental and neuronal phenotypes, we identified multiple homologs that were sensitive to dosage and showed defects in cell proliferation, including KCTD13, MAPK3, and PPP4C. Leveraging the Drosophila eye for studying gene interactions, we performed 561 pairwise knockdowns of gene expression, and identified 24 interactions between 16p11.2 homologs (such as MAPK3 and CORO1A, and KCTD13 and ALDOA) and 62 interactions with other neurodevelopmental genes (such as MAPK3 and PTEN, and KCTD13 and RAF1) that significantly enhanced or suppressed cell proliferation phenotypes. Integration of fly interaction and transcriptome data into a human brain-specific genetic network allowed us to identify 982 novel interactions of 16p11.2 homologs, which were significantly enriched for cell proliferation genes (p=3.14×10 -12 ). Overall, these results point towards a new model for pathogenicity of rare CNVs, where CNV genes interact with each other in conserved pathways to modulate expression of the neurodevelopmental phenotype.

To examine cannulation practice and effectiveness of a multi-modal intervention to reduce peripheral intravenous cannula (PIVC) insertion in emergency department (ED) patients. A prospective before and after study and cost analysis was conducted at a single tertiary ED in Australia. Data were collected 24 hours a day for two weeks pre- and post-implementation of a multi-modal intervention. PIVC placement and utilization within 24 hours were evaluated in all eligible patients. A total of 4,173 participants were included in the analysis. PIVCs were placed in 42.1% of patients' pre-intervention and 32.4% post-intervention, a reduction of 9.8% (95% CI: 6.8 to -12.72%). PIVC usage within 24 hours of admission was 70.5% pre-intervention and 83.4% post-intervention; an increase of 12.9% (95% CI: 8.8-17.0%). Sixty-six patients were observed in the ED for cost analysis. The mean time per PIVC insertion was 15.3 (95% CI: 12.6 - 17.9) minutes. PIVC insertion cost, including staff time and consumables per participant, was A$22.79 (95% CI:A$19.35 - $26.23). The intervention reduced PIVC placement in the ED and increased the percentage of PIVC placed that were used. This program benefits patients and health services alike, with potential for large cost savings. This article is protected by copyright. All rights reserved.

VCU Health Critical Care Transport Network paramedics and nurses staff three rotary-wing aircraft and one ground ambulance that provide scene response and interfacility transports throughout Virginia. Prehospital rapid sequence induction and intubation are among the highest risk procedures employed by these providers, particularly when the airway is massively contaminated with blood or vomit. A quality assurance review of attempted prehospital intubations determined issues with suction to be a key factor in those requiring more than one attempt. A targeted training session introducing Suction Assisted Laryngoscopy and Airway Decontamination (SALAD) was implemented and quality improvement data collected.SALAD was introduced during scheduled quarterly training. In attendance were 15 nurses and 10 paramedics for a total of 25 participants. With no prior notice, training or cognitive priming each participant attempted intubation using videolaryngoscopy on a custom high fidelity training mannequin designed to emit 650 ml per minute of simulated vomit into the airway. Following their first attempt, participants were instructed on SALAD technique by an EMS-fellowship trained emergency physician. Participants then had another opportunity to intubate the mannequin using SALAD technique. Data was collected on number of attempts and time to successful intubation before and after training.Mean time to successful intubation improved from 68.28 seconds to 49.76 seconds (95% confidence interval [CI], -34.976 to -2.064; P = 0.0282). There was a trend toward improvement in mean number of intubation attempts overall from 1.12 per participant to 1.0 (CI, -0.0135 to 0.2535; P = 0.0001). Subgroup analysis, however, found there to be significant improvement for participants whose first attempt time was greater than 91 seconds, from a mean of 127.40 seconds to 53.80 seconds (CI, -116.674 to -30.526; P = 0.043) and 1.6 attempts per participant to 1.0 (CI, -1.165 to -0.0349; P = 0.0400) post intervention.In a controlled environment, SALAD training improves both first pass success and total time to successful intubation. The greatest improvement was observed in the group with the most difficulty and longest time to intubation prior to the targeted educational intervention. This indicates that the introduction of an effective, standardized suction technique for massively contaminated airways can significantly improve quality metrics for intubation by prehospital providers. Further research is needed to determine skill retention and generalizability to an uncontrolled environment.

Background: High mammographic breast density is a strong, well-established breast cancer risk factor. A recent study found increased expression of stem cell markers in the areas of high breast density, but, whether stem cells may explain high breast cancer risk due to high breast density is unknown. We investigated the association between breast density and the risk of breast cancer by the status of stem cell markers CD44, CD24, and ALDH1A1 in the tumor. Methods: We included 223 postmenopausal women with primary invasive or in-situ breast cancer and 399 age-matched controls from Mayo Clinic Mammography Study. Percent breast density, absolute dense area and non-dense area were assessed using computer-assisted thresholding technique. Immunohistochemical analysis of the markers was performed on tumor tissue microarrays according to a standard protocol with commercial antibodies. Cases with positive staining (≥1% positively stained cells) on one or more cores were considered marker-positive. We used polychotomous logistic regression to quantify the associations of breast density measures with breast cancer risk by the status of each of the markers. Heterogeneity tests were conducted to compare the differences in associations by marker-defined tumor subtypes. Results: Of the 223 cancers in the study, 182 (82%) were positive for CD44, 83 (37%) for CD24 and 52 (23%) for ALDH1A1. Associations of percent density were not significantly different across any of the marker-defined subtypes (density 51%+ vs. 11-25%: OR=2.83, 95% CI 1.49-5.37 for CD44+ vs. OR=1.87, 95% CI 0.47-7.51 for CD44-, p-heterogeneity=0.66; OR=2.80, 95% CI 1.27-6.18 for CD24+ vs. OR=2.44, 95% CI 1.14-5.22 for CD24-, p-heterogeneity=0.61; OR=3.04, 95% CI 1.14-8.10 for ALDH1A1+ vs. OR=2.57. 95% CI 1.30-5.08 for ALDH1A1-, p-heterogeneity=0.94). Positive associations of absolute dense area and inverse associations of non-dense area with breast cancer risk were similar across marker-defined subtypes. Similar associations of breast density measures with breast cancer were seen when cancer subtypes were defined using combined marker expression status (none, one positive marker, or two and more positive markers). Conclusions: We found no evidence of differential associations of breast density measures with breast cancer risk by the status of stem cell markers. However, our power was limited and further studies in larger study populations are warranted to confirm these associations in a larger sample. Citation Format: Lusine Yaghjyan, Ashwini Esnakula, Christopher Scott, Akemi Wijayabahu, Matthew Jensen, Celine Vachon. Associations of mammographic breast density with breast stem cell marker-defined breast cancer subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 592.

In the context of practicing intercultural communication skills, we investigated the role of fidelity in a game-based, virtual learning environment as well as the role of feedback delivered by an intelligent tutoring system. In 2 experiments, we compared variations on the game interface, use of the tutoring system, and the form of the feedback. Our findings suggest that for learning basic intercultural communicative skills, a 3-dimensional (3-D) interface with animation and sound produced equivalent learning to a more static 2-D interface. However, learners took significantly longer to analyze and respond to the actions of animated virtual humans, suggesting a deeper engagement. We found large gains in learning across conditions. There was no differential effect with the tutor engaged, but it was found to have a positive impact on learner success in a transfer task. This difference was most pronounced when the feedback was delivered in a more general form versus a concrete style.

Teachers and trainers often try to prevent learners from making errors, but recent findings (e.g., Kornell, Hays, & Bjork, 2009) have demonstrated that tests can potentiate subsequent learning even when the correct answer is difficult or impossible to generate (e.g., "What is Nate Kornell's middle name?"). In 3 experiments, we explored when and why a failed test enhances learning. We found that failed tests followed by immediate feedback produced greater retention than did a presentation-only condition. Failed tests followed by delayed feedback, by contrast, did not produce such a benefit-except when the direction of the final test was reversed (i.e., the participants were provided with the target and had to produce the original cue). Our findings suggest that generating an incorrect response to a cue both activates the semantic network associated with the cue and suppresses the correct response. These processes appear to have 2 consequences: If feedback is presented immediately, the semantic activation enhances the mapping of the cue to the correct response; if feedback is presented at a delay, the prior suppression boosts the learning of the suppressed response.

Whole Exome Sequencing (WES) is a powerful clinical diagnostic tool for discovering the genetic basis of many diseases. A major shortcoming of WES is uneven coverage of sequence reads over the exome targets contributing to many low coverage regions, which hinders accurate variant calling. In this study, we devised two novel metrics, Cohort Coverage Sparseness (CCS) and Unevenness (UE) Scores for a detailed assessment of the distribution of coverage of sequence reads. Employing these metrics we revealed non-uniformity of coverage and low coverage regions in the WES data generated by three different platforms. This non-uniformity of coverage is both local (coverage of a given exon across different platforms) and global (coverage of all exons across the genome in the given platform). The low coverage regions encompassing functionally important genes were often associated with high GC content, repeat elements and segmental duplications. While a majority of the problems associated with WES are due to the limitations of the capture methods, further refinements in WES technologies have the potential to enhance its clinical applications.

Increased global use of motorized vehicles has led to a higher number of automotive crashes involving human injuries and fatalities. Greater driver awareness through haptic feedback can provide vital information from the vehicle and surroundings to the driver while minimizing driver distraction. In this paper, steering wheel haptic feedback will be provided to increase the drivers' knowledge of the roadway and driving conditions. This increased knowledge should enable the driver to avoid obstacles presented in the roadway earlier than without any feedback. A high-fidelity customizable driving simulator was utilized to provide nine different levels of sinusoidal haptic feedback via the steering wheel. Mathematical models for the vehicle steering system, with adjustable controller gains, were developed to create torsional feedback. The testing included 25 human subjects ranging in age and driving experience. Driver preferences for feedback amplitude and frequency were gathered, whereas driver/vehicle performance was used as the measure of feedback effectiveness. The laboratory results demonstrate that haptic steering feedback improved driver performance as measured by a 62% reduction in obstacle hit rates, small reductions in peak steering wheel angle and peak vehicle yaw rate, as well as a nearly 10 m (32.8 ft) increase in reaction distance to the obstacles. The research contribution is the successful application of an advanced steering simulator with a steering control strategy to introduce supplemental haptic feedback to the driver through the steering system for roadway avoidance notification.

Optimizing learning over multiple retrieval opportunities requires a joint consideration of both the probability and the mnemonic value of a successful retrieval. Previous research has addressed this trade-off by manipulating the schedule of practice trials, suggesting that a pattern of increasingly long lags—‘‘expanding retrieval practice’’—may keep retrievals successful while gradually increasing their mnemonic value (Landauer & Bjork, 1978). Here we explore the trade-off issue further using an analogous manipulation of cue informativeness. After being given an initial presentation of English–Inupiaq word pairs, participants received practice trials across which letters of the target word were either accumulated (AC), diminished (DC), or always fully present. Diminishing cues yielded the highest performance on a final test of cued recall. Additional analyses suggest that AC practice promotes potent (effortful) retrieval at the cost of success, and DC practice promotes successful retrieval at the cost of potency. Experiment 2 revealed that the negative effects of AC practice can be partly ameliorated by providing feedback after each practice trial.

It seems uncontroversial that providing feedback after a test, in the form of the correct answer, enhances learning. In real-world educational situations, however, the time available for learning is often constrained— and feedback takes time. We report an experiment in which total time for learning was fixed, thereby creating a trade-off between spending time receiving feedback and spending time on other learning activities. Our results suggest that providing feedback is not universally beneficial. Indeed, under some circumstances, taking time to provide feedback can have a negative net effect on learning. We also found that learners appear to have some insight about the costs of feedback; when they were allowed to control feedback, they often skipped unnecessary feedback in favor of additional retrieval attempts, and they benefited from doing so. These results underscore the importance of considering the costs and benefits of interventions designed to enhance learning.

Taking tests enhances learning. But what happens when one cannot answer a test question-does an unsuccessful retrieval attempt impede future learning or enhance it? The authors examined this question using materials that ensured that retrieval attempts would be unsuccessful. In Experiments 1 and 2, participants were asked fictional general-knowledge questions (e.g., "What peace treaty ended the Calumet War?"). In Experiments 3-6, participants were shown a cue word (e.g., whale) and were asked to guess a weak associate (e.g., mammal); the rare trials on which participants guessed the correct response were excluded from the analyses. In the test condition, participants attempted to answer the question before being shown the answer; in the read-only condition, the question and answer were presented together. Unsuccessful retrieval attempts enhanced learning with both types of materials. These results demonstrate that retrieval attempts enhance future learning; they also suggest that taking challenging tests-instead of avoiding errors-may be one key to effective learning.

We describe the Situated Pedagogical Authoring (SitPed) system that seeks to allow non-technical authors to create ITS content for soft-skills training, such as counseling skills. SitPed is built on the assertion that authoring tools should use the learner’s perspective to the greatest extent possible. SitPed provides tools for creating tasks lists, authoring assessment knowledge, and creating tutor messages. We present preliminary findings of a two-phase study comparing authoring in SitPed to an ablated version of the same system and a spreadsheet-based control. Findings suggest modest advantages for SitPed in terms of the quality of the authored content and student learning.

Advancements in mechatronic system technology has allowed the realization of adjustable automotive steering systems which can better meet customer preferences. Drive-by-wire systems use servo-motors, with accompanying sensors and control algorithms, to regulate the vehicle's operation. In this paper, a multi-modal human-vehicle haptic interface has been developed for ground vehicle steer-by-wire systems. The mathematical model and control structure offer tunable gains that allow the emphasis of different feedback factors including steering stiffness, damping, power assist, aligning torques, end stop, and static friction. Three steering system factors were assessed: control and confidence, ease of use, and perceived vehicle safety. As measured, driver performance improved with the provision of aligning torque plus stiffness and damping effects. Subjective and objective operator-in-the-loop results demonstrated that the driver experience can be positively impacted using a reconfigurable force feedback formulation.

We investigate the role of presence in a serious game for intercultural communication and negotiation skills by comparing two interfaces: a 3D version with animated virtual humans and sound against a 2D version using text-only interactions with static images and no sound. Both versions provide identical communicative action choices and are driven by the same underlying simulation engine. In a study, the 3D interface led to a significantly greater self-reported sense of presence, but produced significant, but equivalent learning on immediate posttests for declarative and conceptual knowledge related to intercultural communication. Log data reveals that 3D learners needed fewer interactions with the system than those in the 2D environment, suggesting they benefited equally with less practice and may have treated the experience as more authentic.