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Sanjhai Ramdeen,1 Brandon Ferrell,1 Christopher Bonk,2 Laura Schubel,2 Robin Littlejohn,2 Muge Capan,3 Ryan Arnold,4 Kristen Miller1,2 1Georgetown University School of Medicine, Washington, DC, USA; 2National Center for Human Factors in Healthcare, MedStar Health Research Institute, Washington, DC, USA; 3Decision Sciences & MIS Department, LeBow College of Business, Drexel University, Philadelphia, PA, USA; 4Department of Emergency Medicine, Drexel University School of Medicine, Philadelphia, PA, USACorrespondence: Kristen MillerNational Center for Human Factors in Healthcare, MedStar Health Research Institute, 3007 Tilden Street NW, Suite 6N, Washington, DC, 20008, USATel +1 2022433873Fax +1 8553449800Email Kristen.E.Miller@medstar.netObjective: The goal of the study was to assess the criteria availability of eight sepsis scoring methods within 6 hours of triage in the emergency department (ED).Design: Retrospective data analysis study.Setting: ED of MedStar Washington Hospital Center (MWHC), a 912-bed urban, tertiary hospital.Patients: Adult (age ≥ 18 years) patients presenting to the MWHC ED between June 1, 2017 and May 31, 2018 and admitted with a diagnosis of severe sepsis with or without shock.Main Outcomes Measured: Availability of sepsis scoring criteria of eight different sepsis scoring methods at three time points— 0 Hours (T0), 3 Hours (T1) and 6 Hours (T2) after arrival to the ED.Results: A total of 50 charts were reviewed, which included 23 (46%) males and 27 (54%) females. Forty-eight patients (96%) were Black or African American. Glasgow Coma Scale was available for all 50 patients at T0. Vital signs, except for temperature, were readily available (> 90%) at T0. The majority of laboratory values relevant for sepsis scoring criteria were available (> 90%) at T1, with exception to bilirubin (66%) and creatinine (80%). NEWS, PRESEP and qSOFA had greater than 90% criteria availability at triage. SOFA and SIRS consistently had the least percent of available criteria at all time points in the ED.Conclusion: The availability of patient data at different time points in a patient’s ED visit suggests that different scoring methods could be utilized to assess for sepsis as more patient information becomes available.Keywords: sepsis, scoring systems, available criteria, emergency department, patient safety, quality improvement

Engineers need considerable understanding of humanities and social science to serve effectively and responsibly as professionals. Undergraduate engineering education faces pressures to add technical and non-technical content and decrease total credit hours, educational costs, and time to degree. This study characterizes how discipline-based engineering programs in the United States distribute required coursework between technical and non-technical areas of study in comparison to math, chemistry, and physics programs; the results could signal consensus or disparity in educational philosophy between and among institutions or disciplines. The distribution of technical versus non-technical coursework was delineated for 103 US News & World Report top-ranked and ABET EAC-accredited undergraduate programs in chemical, civil, electrical, and mechanical engineering based on 2013 catalog requirements, as well as chemistry, math, and physics programs at the same institutions. Technical was defined as coursework in engineering, math or natural science; non-technical was coursework outside of those disciplines. Findings reveal a wide range of required technical and non-technical course loads for all disciplines. For engineering, technical requirements ranged from 62% to 86% (median 75%) of total degree; non-technical requirements ranged from 12% to 35% (median 20%). The math, chemistry, and physics degrees were more balanced between technical and non-technical requirements. Differences in requirements suggest that consensus does not exist amongst engineering educators from this sampling of programs regarding the appropriate allocation of technical versus non-technical coursework for an undergraduate engineering education, and there are substantially divergent interpretations of what constitutes adequate "general education" for an engineer. Additionally, students who desire more well-rounded education might select non-engineering STEM majors. [ABSTRACT FROM AUTHOR]

Heart development is a complex spatiotemporal process involving a series of orchestrated morphogenic events that result in the formation of an efficient pumping organ. How posttranslational mechanisms regulate heart development remains poorly understood. Therefore, we investigate how neddylation, the attachment of NEDD8 to target proteins, coordinates cardiogenesis. Abrogation of neddylation by deleting Nae1 in the heart via Sm22α Cre led to early embryonic lethality. Mutant hearts exhibited deficits in trabeculation and expansion of the compact layer due to reduced cardiomyocyte proliferation, which was linked to abnormal Notch signaling in the developing heart. Overall, our findings demonstrate an essential role for neddylation in cardiogenesis., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Purpose: To evaluate the relative diagnostic yield of clinical germline genomic tests in a diverse pediatric cancer population., Patients and Methods: The KidsCanSeq study enrolled pediatric cancer patients across six sites in Texas. Germline analysis included both exome sequencing and a therapy-focused pediatric cancer gene panel. The results were categorized by participants demographics, the presence of pathogenic or likely pathogenic (P/LP) variants, and variants of uncertain significance (VUS) in cancer predisposition genes (CPGs). Pediatric actionable CPGs were defined as those with cancer surveillance recommendations during childhood., Results: Cancer P/LP variants were reported by at least one platform in 103 of 578 (17.8%) participants of which 76 were dominant cancer genes (13.1%) with no significant differences by self-described race or Hispanic ethnicity. However, the proportion of participants with VUS was greater in Asian and African American participants ( P = .0029). Diagnostic yield was 16.6% for exome versus 8.5% for panel ( P < .0001) with 42 participants with concordant germline results. Exome-only results included P/LP variants in 30 different CPGs in 54 participants, whereas panel-only results included seven participants with a copy number or structural P/LP variants in CPGs. There was no significant difference in diagnostic yield limited to pediatric actionable CPGs ( P = .6171)., Conclusion: Approximately 18% of a diverse pediatric cancer population had germline diagnostic findings with 50% of P/LP variants reported by only one platform because of CPGs not on the targeted panel and copy number variants (CNVs)/rearrangements not reported by exome. Although diagnostic yields were similar in this diverse population, increases in VUS results were observed in Asian and African American populations. Given the clinical significance of CNVs/rearrangements in this cohort, detection is critical to optimize germline analysis of pediatric cancer populations.

Bryant-Li-Bhoj syndrome (BLBS), which became OMIM-classified in 2022 (OMIM: 619720, 619721), is caused by germline variants in the two genes that encode histone H3.3 (H3-3A/H3F3A and H3-3B/H3F3B) [1-4]. This syndrome is characterized by developmental delay/intellectual disability, craniofacial anomalies, hyper/hypotonia, and abnormal neuroimaging [1, 5]. BLBS was initially categorized as a progressive neurodegenerative syndrome caused by de novo heterozygous variants in either H3-3A or H3-3B [1-4]. Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals. In this larger cohort of 96 people, we identify causative missense, synonymous, and stop-loss variants. We also expand upon the phenotypic characterization by elaborating on the neurodevelopmental component of BLBS. Notably, phenotypic heterogeneity was present even amongst individuals harboring the same variant. To explore the complex phenotypic variation in this expanded cohort, the relationships between syndromic phenotypes with three variables of interest were interrogated: sex, gene containing the causative variant, and variant location in the H3.3 protein. While specific genotype-phenotype correlations have not been conclusively delineated, the results presented here suggest that the location of the variants within the H3.3 protein and the affected gene (H3-3A or H3-3B) contribute more to the severity of distinct phenotypes than sex. Since these variables do not account for all BLBS phenotypic variability, these findings suggest that additional factors may play a role in modifying the phenotypes of affected individuals. Histones are poised at the interface of genetics and epigenetics, highlighting the potential role for gene-environment interactions and the importance of future research., (© 2024. The Author(s).)

Purpose: Genomic medicine can end diagnostic odysseys for patients with complex phenotypes; however, limitations in insurance coverage and other systemic barriers preclude individuals from accessing comprehensive genetics evaluation and testing., Methods: The Texome Project is a 4-year study that reduces barriers to genomic testing for individuals from underserved and underrepresented populations. Participants with undiagnosed, rare diseases who have financial barriers to obtaining exome sequencing (ES) clinically are enrolled in the Texome Project., Results: We highlight the Texome Project process and describe the outcomes of the first 60 ES results for study participants. Participants received a genetic evaluation, ES, and return of results at no cost. We summarize the psychosocial or medical implications of these genetic diagnoses. Thus far, ES provided molecular diagnoses for 18 out of 60 (30%) of Texome participants. Plus, in 11 out of 60 (18%) participants, a partial or probable diagnosis was identified. Overall, 5 participants had a change in medical management., Conclusion: To date, the Texome Project has recruited a racially, ethnically, and socioeconomically diverse cohort. The diagnostic rate and medical impact in this cohort support the need for expanded access to genetic testing and services. The Texome Project will continue reducing barriers to genomic care throughout the future study years., Competing Interests: Conflict of Interest Lilei Zhang owns equity and consults for Pelagos Pharmaceuticals, Inc. Scott McLean is a medical consultant for Face2Gene. Baylor College of Medicine (BCM) and Miraca Holdings Inc have formed a joint venture with shared ownership and governance of Baylor Genetics (BG), which performs genetic testing and derives revenue. Pengfei Liu is an employee of BCM and derives support through a professional services agreement with BG. All other authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Social risk factors such as food insecurity and lack of transportation can negatively affect health outcomes, yet implementation of screening and referral for social risk factors is limited in medical settings, particularly in cancer survivorship., Methods: We conducted 18 qualitative, semistructured interviews among oncology teams in 3 health systems in Washington, DC, during February and March 2022. We applied the Exploration, Preparation, Implementation, Sustainment Framework to develop a deductive codebook, performed thematic analysis on the interview transcripts, and summarized our results descriptively., Results: Health systems varied in clinical and support staff roles and capacity. None of the participating clinics had an electronic health record (EHR)-based process for identifying patients who completed their cancer treatment ("survivors") or a standardized cancer survivorship program. Their capacities also differed for documenting social risk factors and referrals in the EHR. Interviewees expressed awareness of the prevalence and effect of social risk factors on cancer survivors, but none employed a systematic process for identifying and addressing social risk factors. Recommendations for increasing screening for social risk factors included designating a person to fulfill this role, improving data tracking tools in the EHR, and creating systems to maintain up-to-date information and contacts for community-based organizations., Conclusion: The complexity of cancer care workflows and lack of reimbursement results in a limited ability for clinic staff members to screen and make referrals for social risk factors. Creating clinical workflows that are flexible and tailored to staffing realities may contribute to successful implementation of a screening and referral program. Improving ongoing communication with community-based organizations to address needs was deemed important by interviewees.

This article describes a method for calculating higher order or nonadiabatic corrections in Born-Oppenheimer theory and its interaction with the translational degrees of freedom. The method uses the Wigner-Weyl correspondence to map nuclear operators into functions on the classical phase space and the Moyal star product to represent operator multiplication on those functions. These are explained in the body of the paper. The result is a power series in κ2, where κ = (m/M)1/4 is the usual Born-Oppenheimer parameter. The lowest order term is the usual Born-Oppenheimer approximation, while higher order terms are nonadiabatic corrections. These are needed in calculations of electronic currents, momenta, and densities. The separation of nuclear and electronic degrees of freedom takes place in the context of the exact symmetries (for an isolated molecule) of translations and rotations, and these, especially translations, are explicitly incorporated into our discussion. This article presents an independent derivation of the Moyal expansion in molecular Born-Oppenheimer theory. We show how electronic currents and momenta can be calculated within the framework of Moyal perturbation theory; we derive the transformation laws of the electronic Hamiltonian, the electronic eigenstates, and the derivative couplings under translations; we discuss in detail the rectilinear motion of the molecular center of mass in the Born-Oppenheimer representation; and we show how the elimination of the translational components of the derivative couplings leads to a unitary transformation that has the effect of exactly separating the translational degrees of freedom., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Objective: The objectives of this study were to (1) examine demographic differences between patient portal users and nonusers; and (2) examine health literacy, patient self-efficacy, and technology usage and attitudes between patient portal users and nonusers., Methods: Data were collected from Amazon Mechanical Turk (MTurk) workers from December 2021 to January 2022. MTurk workers completed an online survey, which asked about their health, access to technology, health literacy, patient self-efficacy, media and technology attitudes, and patient portal use for those with an account. A total of 489 MTurk workers completed the survey. Data were analyzed using latent class analysis (LCA) and multivariate logistic regression models., Results: Latent class analysis models revealed some qualitative differences between users and nonusers of patient portals in relation to neighborhood type, education, income, disability status, comorbidity of any type, insurance type, and the presence or absence of primary care providers. These results were partially confirmed by logistic regression models, which showed that participants with insurance, a primary care provider, or a disability or comorbid condition were more likely to have a patient portal account., Conclusions: Our study findings suggest that access to health care, along with ongoing patient health needs, influence the usage of patient portal platforms. Patients with health insurance have the opportunity to access health care services, including establishing a relationship with a primary care provider. This relationship can be critical to a patient ever creating a patient portal account and actively engaging in their care, including communicating with their care team., Competing Interests: The authors have no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

This paper concerns the representation of angular momentum operators in the Born-Oppenheimer theory of polyatomic molecules and the various forms of the associated conservation laws. Topics addressed include the question of whether these conservation laws are exactly equivalent or only to some order of the Born-Oppenheimer parameter κ = (m/M) 1/4 and what the correlation is between angular momentum quantum numbers in the various representations. These questions are addressed in both problems involving a single potential energy surface and those with multiple, strongly coupled surfaces and in both the electrostatic model and those for which fine structure and electron spin are important. The analysis leads to an examination of the transformation laws under rotations of the electronic Hamiltonian; of the basis states, both adiabatic and diabatic, along with their phase conventions; of the potential energy matrix; and of the derivative couplings. These transformation laws are placed in the geometrical context of the structures in the nuclear configuration space that are induced by rotations, which include the rotational orbits or fibers, the surfaces upon which the orientation of the molecule changes but not its shape, and the section, an initial value surface that cuts transversally through the fibers. Finally, it is suggested that the usual Born-Oppenheimer approximation can be replaced by a dressing transformation, that is, a sequence of unitary transformations that block-diagonalize the Hamiltonian. When the dressing transformation is carried out, we find that the angular momentum operator does not change. This is a part of a system of exact equivalences among various representations of angular momentum operators in Born-Oppenheimer theory. Our analysis accommodates large-amplitude motions and is not dependent on small-amplitude expansions about an equilibrium position. Our analysis applies to noncollinear configurations of a polyatomic molecule; this covers all but a subset of measure zero (the collinear configurations) in the nuclear configuration space.

This article concerns the use of parallel transport to create a diabatic basis. The advantages of the parallel-transported basis include the facility with which Taylor series expansions can be carried out in the neighborhood of a point or a manifold such as a seam (the locus of degeneracies of the electronic Hamiltonian), and the close relationship between the derivative couplings and the curvature in this basis. These are important for analytic treatments of the nuclear Schrödinger equation in the neighborhood of degeneracies. The parallel-transported basis bears a close relationship to the singular-value basis; in this article, both are expanded in power series about a reference point and are shown to agree through second order but not beyond. Taylor series expansions are effected through the projection operator, whose expansion does not involve energy denominators or any type of singularity and in terms of which both the singular-value basis and the parallel-transported basis can be expressed. The parallel-transported basis is a version of Poincaré gauge, well known in electromagnetism, which provides a relationship between the derivative couplings and the curvature and which, along with a formula due to Mead, affords an efficient method for calculating Taylor series of the basis states and the derivative couplings. The case in which fine structure effects are included in the electronic Hamiltonian is covered.

Background and Purpose: Pathogenic somatic variants affecting the genes Histone 3 Family 3A and 3B ( H3F3 ) are extensively linked to the process of oncogenesis, in particular related to central nervous system tumors in children. Recently, H3F3 germline missense variants were described as the cause of a novel pediatric neurodevelopmental disorder. We aimed to investigate patterns of brain MR imaging of individuals carrying H3F3 germline variants., Materials and Methods: In this retrospective study, we included individuals with proved H3F3 causative genetic variants and available brain MR imaging scans. Clinical and demographic data were retrieved from available medical records. Molecular genetic testing results were classified using the American College of Medical Genetics criteria for variant curation. Brain MR imaging abnormalities were analyzed according to their location, signal intensity, and associated clinical symptoms. Numeric variables were described according to their distribution, with median and interquartile range., Results: Eighteen individuals (10 males, 56%) with H3F3 germline variants were included. Thirteen of 18 individuals (72%) presented with a small posterior fossa. Six individuals (33%) presented with reduced size and an internal rotational appearance of the heads of the caudate nuclei along with an enlarged and squared appearance of the frontal horns of the lateral ventricles. Five individuals (28%) presented with dysgenesis of the splenium of the corpus callosum. Cortical developmental abnormalities were noted in 8 individuals (44%), with dysgyria and hypoplastic temporal poles being the most frequent presentation., Conclusions: Imaging phenotypes in germline H3F3- affected individuals are related to brain features, including a small posterior fossa as well as dysgenesis of the corpus callosum, cortical developmental abnormalities, and deformity of lateral ventricles., (© 2022 by American Journal of Neuroradiology.)

Vascular endothelial growth factor receptor type 2 (VEGFR2, also known as KDR and FLK1) signalling in endothelial cells (ECs) is essential for developmental and reparative angiogenesis. Reactive oxygen species and copper (Cu) are also involved in these processes. However, their inter-relationship is poorly understood. Evidence of the role of the endothelial Cu importer CTR1 (also known as SLC31A1) in VEGFR2 signalling and angiogenesis in vivo is lacking. Here, we show that CTR1 functions as a redox sensor to promote angiogenesis in ECs. CTR1-depleted ECs showed reduced VEGF-induced VEGFR2 signalling and angiogenic responses. Mechanistically, CTR1 was rapidly sulfenylated at Cys189 at its cytosolic C terminus after stimulation with VEGF, which induced CTR1-VEGFR2 disulfide bond formation and their co-internalization to early endosomes, driving sustained VEGFR2 signalling. In vivo, EC-specific Ctr1-deficient mice or CRISPR-Cas9-generated redox-dead Ctr1(C187A)-knockin mutant mice had impaired developmental and reparative angiogenesis. Thus, oxidation of CTR1 at Cys189 promotes VEGFR2 internalization and signalling to enhance angiogenesis. Our study uncovers an important mechanism for sensing reactive oxygen species through CTR1 to drive neovascularization., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Defects in protein quality control have been increasingly recognized as pathogenic factors in the development of heart failure, a persistent devastating disease lacking efficacious therapies. Ubiquitin and ubiquitin-like proteins, a family of post-translational modifying polypeptides, play important roles in controlling protein quality by maintaining the stability and functional diversity of the proteome. NEDD8 (neural precursor cell expressed, developmentally downregulated 8), a small ubiquitin-like protein, was discovered two decades ago but until recently the biological significance of NEDD8 modifications (neddylation) in the heart has not been appreciated. In this review, we summarize the current knowledge of the biology of neddylation, highlighting several mechanisms by which neddylation regulates the function of its downstream targets, and discuss the expanding roles for neddylation in cardiac physiology and disease, with an emphasis on cardiac protein quality control. Finally, we outline challenges linked to the study of neddylation in health and disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Li, Zou, Littlejohn, Liu and Su.)

In caring for patients with sepsis, the current structure of electronic health record systems allows clinical providers access to raw patient data without imputation of its significance. There are a wide range of sepsis alerts in clinical care that act as clinical decision support tools to assist in early recognition of sepsis; however, there are serious shortcomings in existing health information technology for alerting providers in a meaningful way. Little work has been done to evaluate and assess existing alerts using implementation and process outcomes associated with health information technology displays, specifically evaluating clinician preference and performance. We developed graphical model displays of two popular sepsis scoring systems, quick Sepsis Related Organ Failure Assessment and Predisposition, Infection, Response, Organ Failure , using human factors principles grounded in user-centered and interaction design. Models will be evaluated in a larger research effort to optimize alert design to improve the collective awareness of high-risk populations and develop a relevant point-of-care clinical decision support system for sepsis.

Clinicians are constantly forecasting patient trajectories to make critical point of care decisions intended to influence clinical outcomes. Little is known, however, about how providers interpret mortality risk against validated scoring systems. This research aims to understand how providers forecast mortality specifically for that of patients with sepsis. Defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, sepsis is commonly hard to diagnose, progresses rapidly, and lacks a "gold standard" test. Participants were nurses and doctors from the general medical and surgical floors of six different hospitals. Each was presented with ten different patient cases, categorized into low and high severity sepsis, and were asked about care decisions, along with estimations of mortality risk. The resulting data provides a unique look into the differences of risk forecasting between profession and patient severity.

The goal of this study was to assess the availability of the criteria of eight sepsis scoring methods (SIRS, NEWS, PRESEP, SOFA, qSOFA, SPEED, MEDS, and PIRO) within six hours of triage in the emergency department (ED). Data was analyzed through a retrospective collection of adult (age >18 years) patients presenting to the MedStar Washington Hospital Center (MWHC) emergency department between June 1, 2017 and May 31, 2018 and admitted with a sepsis or sepsis-related diagnosis that progressed to sepsis before discharge. Vital signs are frequently available upon arrival to the ED, while laboratory values tend to be available within three hours and often are not repeated again within the first six hours after arrival. The availability of patient data at different time points in a patient's ED visit suggests that different scoring methods could be utilized to more effectively diagnose and accurately risk-stratify patients within the sepsis spectrum as more information about the patient becomes available.

Alterations in perinatal conditions (such as preterm birth) is linked to adult health and disease, in particular, the cardiovascular system. Neddylation, a novel posttranslational modification through which the ubiquitin-like protein NEDD8 is conjugated to protein substrates, has emerged as an important mechanism regulating embryonic cardiac chamber maturation. However, the importance of neddylation in postpartum cardiac development has not been investigated. Here, we aimed to determine whether transient, postnatal inhibition of neddylation has immediate and prolonged impact on the structure and function of the neonatal and adult hearts. Sprague-Dawley pups were given three intraperitoneal injections of MLN4924 (MLN), a specific neddylation inhibitor, at postnatal days (P)1, 3, and 5. Cardiac structure and function were temporally assessed during aging and after 2 wk of isoproterenol (ISO) infusion in adulthood. MLN treatment resulted in modest reduction of neddylated proteins in neonatal hearts. The MLN-treated rats developed cardiac hypertrophy and dysfunction by P7, which was accompanied by significantly reduced cardiomyocyte proliferation. At 3 mo of age, cardiac contractile function was restored in MLN-treated rats, but MLN-treated hearts displayed hypertrophic phenotype. Whereas ISO infusion triggered compensatory cardiac hypertrophy without impairing cardiac contractility in the control rats, the MLN-treated rats displayed a similar degree of hypertrophy, which quickly progressed to decompensation with ventricular wall thinning, chamber dilatation, and reduced ejection fraction as well as exacerbated pathological cardiac remodeling. Our findings suggest that neddylation is required for postnatal cardiac development and that perturbation of neddylation during development predisposes adult hearts to cardiac failure under stress conditions. NEW & NOTEWORTHY Our study demonstrates that perinatal perturbation of neddylation induces cardiomyopathy, impairs postnatal cardiac development, and increases susceptibility to catecholamine-induced cardiac dysfunction. The results reveal a previously unappreciated role of neddylation in postnatal cardiac maturation and call for close monitoring for the potential cardiotoxicity of MLN4924 (pevonedistat) and other agents that modify neddylation, especially in pregnant women and preadolescents.

During development, ventricular chamber maturation is a crucial step in the formation of a functionally competent postnatal heart. Defects in this process can lead to left ventricular noncompaction cardiomyopathy and heart failure. However, molecular mechanisms underlying ventricular chamber development remain incompletely understood. Neddylation is a posttranslational modification that attaches ubiquitin-like protein NEDD8 to protein targets via NEDD8-specific E1-E2-E3 enzymes. Here, we report that neddylation is temporally regulated in the heart and plays a key role in cardiac development. Cardiomyocyte-specific knockout of NAE1, a subunit of the E1 neddylation activating enzyme, significantly decreased neddylated proteins in the heart. Mice lacking NAE1 developed myocardial hypoplasia, ventricular noncompaction, and heart failure at late gestation, which led to perinatal lethality. NAE1 deletion resulted in dysregulation of cell cycle-regulatory genes and blockade of cardiomyocyte proliferation in vivo and in vitro, which was accompanied by the accumulation of the Hippo kinases Mst1 and LATS1/2 and the inactivation of the YAP pathway. Furthermore, reactivation of YAP signaling in NAE1-inactivated cardiomyocytes restored cell proliferation, and YAP-deficient hearts displayed a noncompaction phenotype, supporting an important role of Hippo-YAP signaling in NAE1-depleted hearts. Mechanistically, we found that neddylation regulates Mst1 and LATS2 degradation and that Cullin 7, a NEDD8 substrate, acts as the ubiquitin ligase of Mst1 to enable YAP signaling and cardiomyocyte proliferation. Together, these findings demonstrate a role for neddylation in heart development and, more specifically, in the maturation of ventricular chambers and also identify the NEDD8 substrate Cullin 7 as a regulator of Hippo-YAP signaling., Competing Interests: The authors declare no conflict of interest.

Objective: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 ( DNM1 ), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling., Methods: We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function., Results: We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function., Conclusions: The phenotypic spectrum of DNM1 -related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention., (Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: The study objective was to statistically codify empirical occupational fatigue literature into a systems model depicting causal factors of fatigue; interrelationships among causal factors; outcomes of fatigue; and interrelationships among outcomes., Methods: The objective was achieved via a comprehensive and systematic review of existing literature and the first statistical meta-analysis of occupational fatigue., Results: The drivers of fatigue with the greatest effect sizes include sleep deprivation and work environment factors such as noise, vibration, and temperature. The most significant outcomes of fatigue include short-term cognitive and physical degradation and, to a lesser extent, error, injury, and illness., Conclusions: Although there is a great deal of occupational fatigue literature, there is a dearth of replication and validations studies. Researchers are also encouraged to address knowledge gaps like the relationship between worker relationships and fatigue.