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Supplementary Figure 2 from FOXO3 Encodes a Carcinogen-Activated Transcription Factor Frequently Deleted in Early-Stage Lung Adenocarcinoma

Supplementary Figure 4 from FOXO3 Encodes a Carcinogen-Activated Transcription Factor Frequently Deleted in Early-Stage Lung Adenocarcinoma

Supplementary Figure 3 from FOXO3 Encodes a Carcinogen-Activated Transcription Factor Frequently Deleted in Early-Stage Lung Adenocarcinoma

Supplementary Figure 1 from FOXO3 Encodes a Carcinogen-Activated Transcription Factor Frequently Deleted in Early-Stage Lung Adenocarcinoma

The FOXO family of transcription factors elicits cell cycle arrest, apoptosis, and resistance to various physiologic and pathologic stresses relevant to sporadic cancer, such as DNA damage and oxidative stress. Although implicated as tumor suppressors, FOXO genetic inactivation has not been observed in human cancer. In an investigation of the two major types of non–small cell lung cancer, here, we identify the FOXO3 gene as a novel target of deletion in human lung adenocarcinoma (LAC). Biallelic or homozygous deletion (HD) of FOXO3 was detected in 8 of 33 (24.2%) mostly early-stage LAC of smokers. Another 60.6% of these tumors had losses of FOXO3 not reaching the level of HD (hereafter referred to as sub-HD). In contrast, no HD of FOXO3 was observed in 19 lung squamous cell carcinoma. Consistent with the deletion of FOXO3 were corresponding decreases in its mRNA and protein levels in LAC. The potential role of FOXO3 loss in LAC was also investigated. The carcinogen (+)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) is strongly implicated as a cause of human lung cancer. Here, we show that FOXO3a is functionally activated and augments the level of caspase-dependent apoptosis in cells exposed to this DNA-damaging carcinogen. These results implicate FOXO3 as a suppressor of LAC carcinogenesis, a role frequently lost through gene deletion. Cancer Res; 70(15); 6205–15. ©2010 AACR.

The administration of spike monoclonal antibody treatment to patients with mild to moderate COVID-19 is very challenging. This article summarizes essential components and processes in establishing an effective spike monoclonal antibody infusion program. Rapid identification of a dedicated physical infrastructure was essential to circumvent the logistical challenges of caring for infectious patients while maintaining compliance with regulations and ensuring the safety of our personnel and other patients. Our partnerships and collaborations among multiple different specialties and disciplines enabled contributions from personnel with specific expertise in medicine, nursing, pharmacy, infection prevention and control, electronic health record (EHR) informatics, compliance, legal, medical ethics, engineering, administration, and other critical areas. Clear communication and a culture in which all roles are welcomed at the planning and operational tables are critical to the rapid development and refinement needed to adapt and thrive in providing this time-sensitive beneficial therapy. Our partnerships with leaders and providers outside our institutions, including those who care for underserved populations, have promoted equity in the access of monoclonal antibodies in our regions. Strong support from institutional leadership facilitated expedited action when needed, from a physical, personnel, and system infrastructure standpoint. Our ongoing real-time assessment and monitoring of our clinical program allowed us to improve and optimize our processes to ensure that the needs of our patients with COVID-19 in the outpatient setting are met.

We investigated the overall survival (OS), disease-specific survival (DSS), and disease-free survival among patients with oral lichen planus-associated oral cavity squamous cell carcinoma (OLP-OCSCC). The secondary objective was to assess the annual risk of tumor recurrence or second primary tumor (SPT).A comparative retrospective study was performed of patients with OLP-OCSCC presenting between June 2007 and December 2018 to the Department of Oral and Maxillofacial Surgery, Michigan Medicine (Ann Arbor, MI) and patients with OCSCC in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database (1973 to 2015).A total of 87 patients with OLP-OCSCC met the inclusion criteria, and 55,165 patients with OCSCC from the SEER database were included. The proportion of women was greater in the OLP group than in the SEER group (56.3 vs 38.0%; P .001). In the OLP group, 47.1% had no smoking history and 43.7% had no alcohol history. Most patients in the OLP group had presented with stage I disease (46.0%) compared with 31.7% in the SEER group (P = .004). Overall, the OS and DSS were significantly greater in the OLP group than in the SEER group at all points from 1 to 5 years (P ≤ .01). In the OLP group, 46 patients (52.9%) had at least 1 recurrence or SPT. At 10 years, the predicted mean number of recurrences was 1.93 per patient (95% confidence interval, 1.56 to 2.39).OLP-OCSCC frequently affects women, nonsmokers, and nondrinkers and presents with localized disease at a high frequency. Patients with OLP-OCSCC have increased OS and DSS and a greater risk of tumor recurrence or SPT compared with OCSCC in the general population. Lifelong, frequent surveillance is recommended for patients with OLP-OCSCC owing to the risk of late recurrence. Future studies are needed to understand the pathophysiology of OLP-OCSCC.

Biallelic pathogenic variants in the gene PYROXD1 have recently been described to cause early‐onset autosomal recessive myopathy. Myopathy associated with PYROXD1 pathogenic variants is rare and reported in only 17 individuals. Known pathogenic variants in PYROXD1 include missense, insertion and essential splice‐site variants. Here we describe a consanguineous family of individuals affected with late‐onset myopathy and homozygous PYROXD1 missense variants (NM_024854.5:c.464A>G [p.Asn155Ser]) expanding our understanding of the possible disease phenotypes of PYROXD1‐associated myopathy.

Many of the most challenging issues military members and their families are facing are trauma related. Agencies and treatment providers working with military members and their families shou...

MCrAlY (M = Ni, Co) coatings are commonly used on gas-turbine components as oxidation resistant overlay coatings and bondcoats for thermal barrier systems. The present work focuses on the effect of the aluminizing process on the CoNiCrAlY coating microstructure. In the as-received condition the outer part of the coating consisted mostly of β-(Ni,Co)Al with interspersed precipitates of Cr-rich carbide and Cr-rich boride precipitates. Formation of σ-CoCr was observed at the interface between the β-layer and the inner initial CoNiCrAlY microstructure. Scanning electron microscopy (SEM) combined with energy and wavelength-dispersive X-ray spectroscopy (EDX/WDX) was employed to characterize the aluminized CoNiCrAlY coating. Phases were then identified by electron backscatter diffraction (EBSD). Detailed microstructural studies of the coating were corroborated with the help of coupled thermodynamic-kinetic calculations to model the aluminizing process. The calculations were performed with the in-house developed code employing the commercially available thermodynamic and kinetic databases (ThermoCalc). The mechanisms of the observed microstructural changes were elucidated with the help of the modelling results.

Up to 75 % of the overall work piece error can be caused by the thermo-elastic behavior of the machine tool. Therefore, correction methods based on machine-integrated sensors were intensively researched during the last years, in order to determine the error of the Tool Center Point (TCP) parallel to the process. One of these methods includes the integral deformation sensor (IDS), which detects the deformation along the length of a structural component of the machine. The error of the TCP is modelled based on the measured structural deformations, a mechanical model of the structural parts and a kinematic model of the machine tool. Currently, the sensor setup for specific machines is usually defined by an expert with the help of his or her domain knowledge. There are existing mathematical methods for optimal sensor positioning. The aim of this work is the evaluation of the expert positioning versus the mathematical methods. The parameters to be varied are the lengths and positions of the IDS. Criteria for the evaluation are the achievable accuracy of the TCP error prediction and the sensitivity to small variations of the optimal position, as they might occur during the installation.

Exome or genome sequencing was performed to identify the genetic etiology for the clinical presentation of global developmental delay, intellectual disability, and sensorimotor neuropathy with associated distal weakness in two unrelated families. A homozygous frameshift variant c.186delA (p.A63Qfs*3) in the NUDT2 gene was identified in cases 1 and 2 from one family and a third case from another family. Variants in NUDT2 were previously shown to cause intellectual disability, but here we expand the phenotype by demonstrating its association with distal upper and lower extremity weakness due to a sensorimotor polyneuropathy with demyelinating and/or axonal features.

Contains fulltext : 202800.pdf (Publisher’s version ) (Open Access) SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.

Kistenwaschmaschinen sind in der Lebensmittelindustrie, insbesondere in der Fleischbranche eine der dominanten Schallquellen und mitverantwortlich für das Krankheitsbild der berufsbedingten Lärmschwerhörigkeit (Berufskrankheit Nr. 2301). Entsprechend lärmgeminderte Anlagen werden beim Einkauf zu selten nachgefragt. Hersteller sind nach EG-Maschinenrichtlinie (2006/42/EG) verpflichtet, Schallemissionswerte (sog. Geräuschemissionsangaben) gleichwertig zu sonstigen Leistungsangaben in entsprechenden Verkaufsprospekten, Bedienungsanleitungen als auch auf Internetportalen anzugeben (Tabelle 1). Nur dadurch wird dem Arbeitgeber als Maschinenbetreiber die Möglichkeit gegeben, seiner Pflicht, geräuscharme Produktionsmittel nach dem Stand der Technik einzusetzen, nachzukommen. Die Alternative der nachträglichen Lärmminderung ist zwar möglich, aber immer mit zusätzlichen Kosten und Aufwand verbunden. Summary Crate washing machines are one of the dominant sound sources in the food industry, especially in the meat industry, and responsible for the clinical picture of occupational noise-induced deafness (occupational disease No. 2301). Accordingly, quiet systems are rarely in demand when shopping. Manufacturers are required by the EC Machinery Directive (2006/42/EC) to specify sound emission values (so-called noise emission data) equivalent to other performance data in corresponding sales prospectuses, operating instructions and on Internet portals (table 1). Only in this way is the employer, as machine operator, given the opportunity to fulfill his duty to use low-noise production equipment according to the state of the art. The alternative of the subsequent noise abatement is possible but partly associated with additional costs and effort.

Neurodevelopmental disorders (NDD) are genetically and phenotypically heterogeneous conditions due to defects in genes involved in development and function of the nervous system. Individuals with NDD, in addition to their primary neurodevelopmental phenotype, may also have accompanying syndromic features that can be very helpful diagnostically especially those with recognizable facial appearance. In this study, we describe ten similarly affected individuals from six unrelated families of different ethnic origins having bi-allelic truncating variants in TMEM94, which encodes for an uncharacterized transmembrane nuclear protein that is highly conserved across mammals. The affected individuals manifested with global developmental delay/intellectual disability, and dysmorphic facial features including triangular face, deep set eyes, broad nasal root and tip and anteverted nostrils, thick arched eye brows, hypertrichosis, pointed chin, and hypertelorism. Birthweight in the upper normal range was observed in most, and all but one had congenital heart defects (CHD). Gene expression analysis in available cells from affected individuals showed reduced expression of TMEM94. Global transcriptome profiling using microarray and RNA sequencing revealed several dysregulated genes essential for cell growth, proliferation and survival that are predicted to have an impact on cardiotoxicity hematological system and neurodevelopment. Loss of Tmem94 in mouse model generated by CRISPR/Cas9 was embryonic lethal and led to craniofacial and cardiac abnormalities and abnormal neuronal migration pattern, suggesting that this gene is important in craniofacial, cardiovascular, and nervous system development. Our study suggests the genetic etiology of a recognizable dysmorphic syndrome with NDD and CHD and highlights the role of TMEM94 in early development.

For decades, dental schools in the United States have endured a significant faculty shortage. Studies have determined that the top 2 sources of dental faculty are advanced education programs and private practice. Those who have completed both DDS and PhD training are considered prime candidates for dental faculty positions. However, there is no national database to track those trainees and no evidence to indicate that they entered academia upon graduation. The objective of this study was to assess outcomes of dental school–affiliated oral sciences PhD program enrollment, graduates, and placement between 1994 and 2016. Using the American Dental Association annual survey of advanced dental education programs not accredited by the Commission on Dental Accreditation and data obtained from 22 oral sciences PhD programs, we assessed student demographics, enrollment, graduation, and placement. Based on the data provided by program directors, the average new enrollment was 33, and graduation was 26 per year. A total of 605 graduated; 39 did not complete; and 168 were still in training. Among those 605 graduates, 211 were faculty in U.S. academic institutions, and 77 were faculty in foreign institutions. Given that vacant budgeted full-time faculty positions averaged 257 per year during this period, graduates from those oral sciences PhD programs who entered academia in the United States would have filled 9 (3.6%) vacant faculty positions per year. Therefore, PhD programs have consistently generated only a small pipeline of dental school faculty. Better mentoring to retain talent in academia is necessary. Stronger support and creative funding plans are essential to sustain the PhD program. Furthermore, the oral sciences PhD program database should be established and maintained by dental professional organizations to allow assessments of training models, trends of enrollment, graduation, and placement outcomes.

Why is hypocrisy so pervasive in our political, professional, and personal lives? Existing research on hypocrisy suggests that word-deed misalignment is penalized. Yet, hypocrisy continues to perme...

MCrAlY (M = Ni, Co) coatings are commonly used on gas-turbine components as oxidation resistant overlay coatings and bondcoats for thermal barrier systems. In the present work the microstructural f...

The high rate of re-hospitalization for heart failure might be reduced by improving noninvasive techniques for identifying elevated left ventricular (LV) filling pressure. We previously showed that changes in a finger photoplethysmography (PPG) waveform during the Valsalva maneuver (VM) reflect invasively measured LV end-diastolic pressure (LVEDP). We have since developed a hand-held device that analyzes PPG while guiding the expiratory effort of a VM. Here we assessed the sensitivity and specificity of this device for identifying elevated LVEDP in patients. We tested 82 participants (28 women), aged 40 to 85 years, before a clinically indicated left heart catheterization. Each performed a VM between 18 and 25 mm Hg for 10 seconds into a pressure transducer. PPG was recorded continuously before and during the VM. LVEDP was measured during the catheterization. An equation for calculating LVEDP was derived using (1) ratio of signal amplitudes: minimum during VM to average at baseline, (2) ratio of peak-to-peak time intervals: minimum during VM to average at baseline, and (3) mean blood pressure. Calculated and measured LVEDP were compared. The range of measured LVEDP was 4 to 35 mm Hg. Calculated LVEDP correlated with measured LVEDP (p0.0001, r = 0.56). A calculated LVEDP20 mm Hg had a 70% sensitivity and 86% specificity for identifying measured LVEDP20 mm Hg (area under receiver-operating characteristic curve 0.83). In conclusion, a hand-held device for assessing LV filling pressure had high specificity and good sensitivity for identifying LVEDP20 mm Hg, a clinically meaningful threshold in heart failure.

During the course of previous military conflicts, attention has been focused on separations experienced by service members and their loved ones. This study utilized the ABC-X model of Family Stress...

Diagnosis at the edges of our knowledge calls upon clinicians to be data driven, cross-disciplinary, and collaborative in unprecedented ways. Exact disease recognition, an element of the concept of precision in medicine, requires new infrastructure that spans geography, institutional boundaries, and the divide between clinical care and research. The National Institutes of Health (NIH) Common Fund supports the Undiagnosed Diseases Network (UDN) as an exemplar of this model of precise diagnosis. Its goals are to forge a strategy to accelerate the diagnosis of rare or previously unrecognized diseases, to improve recommendations for clinical management, and to advance research, especially into disease mechanisms. The network will achieve these objectives by evaluating patients with undiagnosed diseases, fostering a breadth of expert collaborations, determining best practices for translating the strategy into medical centers nationwide, and sharing findings, data, specimens, and approaches with the scientific and medical communities. Building the UDN has already brought insights to human and medical geneticists. The initial focus has been on data sharing, establishing common protocols for institutional review boards and data sharing, creating protocols for referring and evaluating patients, and providing DNA sequencing, metabolomic analysis, and functional studies in model organisms. By extending this precision diagnostic model nationally, we strive to meld clinical and research objectives, improve patient outcomes, and contribute to medical science.

Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 ( NACC1 ) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10 −14 ). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1 .

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.

Background Despite growing evidence of diagnostic yield and clinical utility of whole exome sequencing (WES) in patients with undiagnosed diseases, there remain significant cost and reimbursement barriers limiting access to such testing. The diagnostic yield and resulting clinical actions of WES for patients who previously faced insurance coverage barriers have not yet been explored. Methods We performed a retrospective descriptive analysis of clinical WES outcomes for patients facing insurance coverage barriers prior to clinical WES and who subsequently enrolled in the Undiagnosed Diseases Network (UDN). Clinical WES was completed as a result of participation in the UDN. Payer type, molecular diagnostic yield, and resulting clinical actions were evaluated. Results Sixty-six patients in the UDN faced insurance coverage barriers to WES at the time of enrollment (67% public payer, 26% private payer). Forty-two of 66 (64%) received insurance denial for clinician-ordered WES, 19/66 (29%) had health insurance through a payer known not to cover WES, and 5/66 (8%) had previous payer denial of other genetic tests. Clinical WES results yielded a molecular diagnosis in 23 of 66 patients (35% [78% pediatric, 65% neurologic indication]). Molecular diagnosis resulted in clinical actions in 14 of 23 patients (61%). Conclusions These data demonstrate that a substantial proportion of patients who encountered insurance coverage barriers to WES had a clinically actionable molecular diagnosis, supporting the notion that WES has value as a covered benefit for patients who remain undiagnosed despite objective clinical findings.

Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourinary abnormalities. The de novo variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model. Our findings indicate that mutations in EBF3 cause a genetic neurodevelopmental syndrome and suggest that loss of EBF3 function might mediate a subset of neurologic phenotypes shared by ARX-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations.

Ultrasound techniques are able to provide a fairly complete examination of the urinary system, achieving a high sensitivity in relevant-pathology detection, especially in the kidney, bladder and prostate. Early detection of pathologies such as tumors or urinary tract obstructions, sometimes even before their clinical manifestation, has improved their management and prognosis in many cases. This, added to its low cost and harmlessness, makes ultrasound ideal for early approaches and follow-up of a wide number of urinary system pathologies. In this article, the ultrasound characteristics of the main urinary system pathologies that can be diagnosed by this technique, are reviewed.

Fentanyl is a potent opiate commonly administered during cardiac catheterization procedures in North America.1 The question of whether fentanyl could have adverse consequences in patients undergoing percutaneous coronary intervention (PCI) is raised by recent research demonstrating that intravenous morphine significantly delays the absorption of oral P2Y12 platelet inhibitors.2 The presumed mechanism is slowed gastric emptying. The single-center PACIFY trial (Platelet Aggregation With Ticagrelor Inhibition and Fentanyl; ClinicalTrials.gov. Unique identifier: NCT02683707) randomized adults undergoing clinically indicated elective coronary angiography to receive the procedure with or without intravenous fentanyl.3 The study was approved by the Johns Hopkins Medicine Institutional Review Board, and all participants provided written informed consent. Eligible adults had not received P2Y12 inhibitors for 14 days before enrollment. Other exclusion criteria included preprocedural treatment with oral anticoagulants or opiates, platelet count

Interferon regulatory factor 2 binding protein-like (IRF2BPL) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals who carry damaging heterozygous variants in IRF2BPL and are affected with neurological symptoms. Five individuals who carry IRF2BPL nonsense variants resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The IRF2BPL bioinformatics signature based on population genomics is consistent with a gene that is intolerant to variation. We show that the fruit-fly IRF2BPL ortholog, called pits (protein interacting with Ttk69 and Sin3A), is broadly detected, including in the nervous system. Complete loss of pits is lethal early in development, whereas partial knockdown with RNA interference in neurons leads to neurodegeneration, revealing a requirement for this gene in proper neuronal function and maintenance. The identified IRF2BPL nonsense variants behave as severe loss-of-function alleles in this model organism, and ectopic expression of the missense variants leads to a range of phenotypes. Taken together, our results show that IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.

PurposeMixoploidy is a type of mosaicism where an organism is a mixture of cells with different numbers of chromosomes. There are a broad range of phenotypes associated with mixoploidy that vary greatly depending on the fraction of cells that are non-diploid, their chromosome number, their distribution, and presumably the specific variation present in the patient. Clinical detection of mixoploidy is important for diagnosis.MethodsWe developed a method to detect mixoploidy from clinical whole genome sequencing (WGS) data through the identification of excess of variant calls centered on unusual B-allele frequencies. Our method isolates the signal from these variants using trio calls and then solves a basic linear equation to estimate levels of diploid-triploid mixoploidy within the sample.ResultsWe show that our method reflects the results from a cytogenetic test. We provide examples detailing how our method has been used to identify diploid-triploid mixoploid individuals from within the NIH Undiagnosed Diseases Network. We present confirmatory findings obtained by clinical cytogenetic testing and show that our method can be used to identify the diploid-triploid ratio in these cases.ConclusionWGS data from patients with rare diseases can be used to identify mixoploid individuals. Individuals with certain characteristics as discussed should be tested for mixoploidy as part of standard clinical pipeline procedures. Scripts that perform this calculation are publicly available athttps://github.com/HudsonAlpha/mixoviz.

Purpose Sixty-75% of individuals with rare and undiagnosed phenotypes remain undiagnosed after whole exome sequencing (ES). With standard ES reanalysis resolving 10–15% of the ES negatives, further approaches are necessary to maximize diagnoses in these individuals. Methods In 38 ES negative patients an individualized genomic-phenotypic approach was employed utilizing: A) Phenotyping; B) Reanalyses of FASTQ files, with innovative bioinformatics; C) Targeted molecular testing; D) Whole genome sequencing (WGS) and E) Conferring of clinical diagnoses when pathognomonic clinical findings occurred. Results Certain and Highly Likely diagnoses were made in 18/38 (47%) individuals, including identifying two new developmental disorders. The majority of diagnoses (>70%) were due to our bioinformatics, phenotyping and targeted testing identifying variants that were undetected or not prioritized on prior ES. WGS diagnosed 3/18 individuals, with structural variants not amenable to ES. Additionally, Tentative diagnoses were made in three (8%) and in five individuals (13%) candidate genes were identified. Overall, diagnoses/potential leads were identified in 26/38 (68%). Conclusions Our comprehensive approach to ES negatives maximizes the ES and clinical data for both diagnoses and candidate gene identification, without WGS in the majority. This iterative approach is cost-effective and is pertinent to the current conundrum of ES negatives.

The Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) gene encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals affected with neurological symptoms who carry damaging heterozygous variants in IRF2BPL. Five cases carrying nonsense variants in IRF2BPL resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The bioinformatics signature for IRF2BPL based on population genomics is consistent with a gene that is intolerant to variation. We show that the IRF2BPL ortholog in the fruit fly, called pits (protein interacting with Ttk69 and Sin3A), is broadly expressed including the nervous system. Complete loss of pits is lethal early in development, whereas partial knock-down with RNA interference in neurons leads to neurodegeneration, revealing requirement for this gene in proper neuronal function and maintenance. The nonsense variants in IRF2BPL identified in patients behave as severe loss-of-function alleles in this model organism, while ectopic expression of the missense variants leads to a range of phenotypes. Taken together, IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.

Based on the method of adaptive finite elements (FEM) a correction approach has been considered to identify the influence of thermo-elastic workpiece deformations during the production process milling. The paper presents a simulation-based tolerance variation calculation of cutting paths, which is caused by the heat input of the machine tool. Therefore a mathematical method is developed to numerically depict the progress of the miller with different curves A(t), B(t) and C(t). These curves are used to map the state of the milling path during the production process as well as to compare the current workpiece contour and the target workpiece contour. The tool center point (TCP) correction results from mapping of time-dependent deformation fields from the FE simulation. The aim is, on the one hand, to make statements before the production about keeping the tolerance, and on the other hand, to derive other correction approaches for the adaption of the cutting path coordinates.

In this case report of autosomal recessive pigmented hypomaturation amelogenesis imperfecta (AI), we identify a novel homozygous missense mutation (g.165151 T>G; c.1317 T>G; p.Leu436 Arg) in SLC24A4, a gene encoding a potassium-dependent sodium-calcium exchanger that is critical for hardening dental enamel during tooth development.

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.

One major challenge encountered with interpreting human genetic variants is the limited understanding of the functional impact of genetic alterations on biological processes. Furthermore, there remains an unmet demand for an efficient survey of the wealth of information on human homologs in model organisms across numerous databases. To efficiently assess the large volume of publically available information, it is important to provide a concise summary of the most relevant information in a rapid user-friendly format. To this end, we created MARRVEL (model organism aggregated resources for rare variant exploration). MARRVEL is a publicly available website that integrates information from six human genetic databases and seven model organism databases. For any given variant or gene, MARRVEL displays information from OMIM, ExAC, ClinVar, Geno2MP, DGV, and DECIPHER. Importantly, it curates model organism-specific databases to concurrently display a concise summary regarding the human gene homologs in budding and fission yeast, worm, fly, fish, mouse, and rat on a single webpage. Experiment-based information on tissue expression, protein subcellular localization, biological process, and molecular function for the human gene and homologs in the seven model organisms are arranged into a concise output. Hence, rather than visiting multiple separate databases for variant and gene analysis, users can obtain important information by searching once through MARRVEL. Altogether, MARRVEL dramatically improves efficiency and accessibility to data collection and facilitates analysis of human genes and variants by cross-disciplinary integration of 18 million records available in public databases to facilitate clinical diagnosis and basic research.

Cognitive appraisal and coping theory were used to examine parental stress, family stress, and personal stress among wives of deployed soldiers. A random sample of wives of U.S. Army personnel deployed to Iraq provided evidence that length of deployment, rank of deployed soldier, and number of previous deployments, impacted these wives during deployments. Results suggest that rank of deployed soldiers and number of deployments influenced the spouse's perception of family stress; whereas rank and length of the deployment influenced her experience of parental stress. All three factors served as indicators of the personal stress experienced during deployments by these wives.

Anamnese und klinischer Befund: Ein 43-jahriger Mann kam mit progredienter Dyspnoe, Husten und Auswurf in unsere Notfallstation. Eine symptomatische Therapie hatte bislang zu keiner Besserung gefuhrt. Klinisch prasentierte er sich in einem reduzierten Allgemeinzustand mit deutlicher Tachypnoe. Entsprechende Episoden waren seit seiner Jugend bekannt. Untersuchungen: Eine ausfuhrliche Diagnostik zur Evaluation der Dyspnoe und Infektsuche erbrachte eine leichtgradige Erhohung der Entzundungsparameter mit einem CRP von 26 mg/l. Die arterielle Blutgasanalyse zeigte eine mittelschwere respiratorische Partialinsuffizienz mit einem pO 2 von 8,35 kPa (63 mmHg) und einem pCO 2 von 3,84 kPa (29 mmHg). Diagnose, Therapie und Verlauf: Computertomographisch konnte die Diagnose einer Tracheobronchomegalie gestellt werden. Diese seltene Ursache rezidivierender Bronchitiden ist nach ihrem Erstbeschreiber Mounier-Kuhn benannt. Bronchoskopisch wurde die Diagnose einer schweren eitrigen Bronchitis bestatigt. Unter antibiotischer und inhalativer Therapie mit Bronchodilatatoren gingen die Symptome rasch zuruck. Folgerung: Bei Patienten mit rezidivierenden Bronchitiden muss an eine zugrunde liegende Pathologie des Tracheobronchialbaums gedacht werden. Das Mounier-Kuhn-Syndrom wird oft nicht erkannt, da die Diagnose im konventionellen Rontgenbild nicht gestellt werden kann. Goldstandard in der Diagnostik ist die Computertomographie. Die Erkrankung ist auserst komplikationstrachtig und fuhrt unbehandelt nicht selten zu schwerer Ateminsuffizienz und Tod.

High temperature superconductors, especially rare-earth barium copper oxide (REBa₂Cu₃O₇₋ₓ or REBCO) tapes are an enabling technology for magnetic fields beyond 23.5 T, the limit of the existing technology based on the low temperature superconductors (LTS) niobium–titanium (NbTi) and niobium–tin (Nb₃Sn). Due to their higher prices, REBCO tapes are in general only employed as insert coils in an LTS outsert. Due to the tape geometry, the effect of the screening currents is high in REBCO insert coils. The resulting screening current-induced field (SCIF) can distort the shape and magnitude as well as affect the temporal stability of the field after charging. Their influence has to be well understood and it can be a limiting factor in field quality critical applications such as nuclear magnetic resonance magnets. In this work, we present the test results of a layer-wound 4 T REBCO insert coil operated in the background of a 21 T LTS outsert reaching a combined field of 25 T. Using an array of 13 calibrated Hall sensors, we investigate the spatial and temporal effects of the SCIFs at different background fields. Series expansion is employed to separate the contributions of the insert and of the outsert. We present in this work the characterization of the effect of the SCIF on the shape of the field and on its temporal stability in background fields from 0 T up to 19 T. We compare the experimental results with existing simulation models for the validation of the model at high magnetic fields, which had never been done for layer-wound REBCO coils. Based on the experimental data, we demonstrate the necessity of SCIF-aware simulations for REBCO insert coils, regardless of the insert's relative operating current. Before summarizing and concluding the work, we give a short overview of proposed methods for SCIF reduction in REBCO coils from the literature.

This qualitative study explores veteran treatment court (VTC) participant perceptions of the judicial processes within the court, their experiences with the judge and other court actors, and the relationship between their military service and criminal activity. Purposive sampling was employed to recruit a sample of 13 justice-involved veterans, who at the time of interviewing, were being adjudicated in a VTC located in the southeastern United States. Semi-structured interviewing was used to capture veteran perceptions of VTC. Five unique themes emerged, while perceptions of court actors and the connection between their military service and crime had three themes, respectively. From these themes, we developed a maladaptive coping model to illustrate the experiences of veterans in veteran courts. The study results are intended to inform policy makers, judicial actors, and veteran service providers as they design judicial responses for veteran offenders.

Veterans and their family members may need clinical services from social workers or other mental health practitioners, but that is not likely their first stop in trying to secure assistance. Instead, they may seek help through their benefit claims or try to find resources from local community organizations. However, volunteers who staff these organizations may have limited exposure to military or veteran populations and lack training in interviewing, assessment, and case management. This is especially true in rural areas or communities that are not in close proximity to military bases or Veterans Affairs facilities. A veteran certificate program based on a social work curriculum can respond to those knowledge gaps and improve basic intervention skills. A newly implemented veteran certificate program using practice-based scenarios is described along with a review of implementation issues, participant outcomes, and recommendations for future needs.

Rural social work occurs in unique practice environments with challenges and rare opportunities. Strong social ties, commonly found in rural communities and often missing in urban areas, can serve as sources of resilience for group members facing adverse life circumstances. Therapeutic formal and informal support groups, bolstered by this support and led by social workers in rural communities, can face numerous challenges due to locale, lack of transportation, and potential worker burnout. This article highlights ethical considerations rooted in a theme of rural group work while providing helpful hints based on the IASWG Standards for Social Work Practice with Groups.

Andreas R. Herzog setzt sich in Kap. 16 mit der Innenpositionierung zur Geschaftsleitung auseinander. Zuerst beschaftigt er sich mit dem Aufgabenportfolio der Rechtsabteilung. Danach erlautert er detailliert die Erwartungen der Unternehmensleitung an ihre Rechtsabteilung und zeigt absolute No-Gos auf. Schlieslich nimmt der Autor Stellung zur Frage des Legal Outsourcings aus Sicht der Geschaftsleitung.