Personal omics profiling reveals dynamic molecular and medical phenotypes.

Personalized medicine is expected to benefit from combining genomic information with regular monitoring of physiological states by multiple high-throughput methods. Here, we present an integrative personal omics profile (iPOP), an analysis that combines genomic, transcriptomic, proteomic, metabolomic, and autoantibody profiles from a single individual over a 14 month period. Our iPOP analysis revealed various medical risks, including type 2 diabetes. It also uncovered extensive, dynamic changes in diverse molecular components and biological pathways across healthy and diseased conditions. Extremely high-coverage genomic and transcriptomic data, which provide the basis of our iPOP, revealed extensive heteroallelic changes during healthy and diseased states and an unexpected RNA editing mechanism. This study demonstrates that longitudinal iPOP can be used to interpret healthy and diseased states by connecting genomic information with additional dynamic omics activity.

Surgical Trainee Performance and Alignment With Surgical Program Director Expectations.

OBJECTIVE: To examine the alignment between graduating surgical trainee operative performance and a prior survey of surgical program director expectations. BACKGROUND: Surgical trainee operative training is expected to prepare residents to independently perform clinically important surgical procedures. METHODS: We conducted a cross-sectional observational study of US general surgery residents' rated operative performance for Core general surgery procedures. Residents' expected performance on those procedures at the time of graduation was compared to the current list of Core general surgery procedures ranked by their importance for clinical practice, as assessed via a previous national survey of general surgery program directors. We also examined the frequency of individual procedures logged by residents over the course of their training. RESULTS: Operative performance ratings for 29,885 procedures performed by 1861 surgical residents in 54 general surgery programs were analyzed. For each Core general surgery procedure, adjusted mean probability of a graduating resident being deemed practice-ready ranged from 0.59 to 0.99 (mean 0.90, standard deviation 0.08). There was weak correlation between the readiness of trainees to independently perform a procedure at the time of graduation and that procedure's historical importance to clinical practice ( p = 0.22, 95% confidence interval 0.01-0.41, P = 0.06). Residents also continue to have limited opportunities to learn many procedures that are important for clinical practice. CONCLUSION: The operative performance of graduating general surgery residents may not be well aligned with surgical program director expectations.

Early somatic mosaicism is a rare cause of long-QT syndrome.

Somatic mosaicism, the occurrence and propagation of genetic variation in cell lineages after fertilization, is increasingly recognized to play a causal role in a variety of human diseases. We investigated the case of life-threatening arrhythmia in a 10-day-old infant with long QT syndrome (LQTS). Rapid genome sequencing suggested a variant in the sodium channel NaV1.5 encoded by SCN5A, NM_000335:c.5284G > T predicting p.(V1762L), but read depth was insufficient to be diagnostic. Exome sequencing of the trio confirmed read ratios inconsistent with Mendelian inheritance only in the proband. Genotyping of single circulating leukocytes demonstrated the mutation in the genomes of 8% of patient cells, and RNA sequencing of cardiac tissue from the infant confirmed the expression of the mutant allele at mosaic ratios. Heterologous expression of the mutant channel revealed significantly delayed sodium current with a dominant negative effect. To investigate the mechanism by which mosaicism might cause arrhythmia, we built a finite element simulation model incorporating Purkinje fiber activation. This model confirmed the pathogenic consequences of cardiac cellular mosaicism and, under the presenting conditions of this case, recapitulated 2:1 AV block and arrhythmia. To investigate the extent to which mosaicism might explain undiagnosed arrhythmia, we studied 7,500 affected probands undergoing commercial gene-panel testing. Four individuals with pathogenic variants arising from early somatic mutation events were found. Here we establish cardiac mosaicism as a causal mechanism for LQTS and present methods by which the general phenomenon, likely to be relevant for all genetic diseases, can be detected through single-cell analysis and next-generation sequencing.

Readiness of US General Surgery Residents for Independent Practice.

OBJECTIVE: This study evaluates the current state of the General Surgery (GS) residency training model by investigating resident operative performance and autonomy. BACKGROUND: The American Board of Surgery has designated 132 procedures as being "Core" to the practice of GS. GS residents are expected to be able to safely and independently perform those procedures by the time they graduate. There is growing concern that not all residents achieve that standard. Lack of operative autonomy may play a role. METHODS: Attendings in 14 General Surgery programs were trained to use a) the 5-level System for Improving and Measuring Procedural Learning (SIMPL) Performance scale to assess resident readiness for independent practice and b) the 4-level Zwisch scale to assess the level of guidance (ie, autonomy) they provided to residents during specific procedures. Ratings were collected immediately after cases that involved a categorical GS resident. Data were analyzed using descriptive statistics and supplemented with Bayesian ordinal model-based estimation. RESULTS: A total of 444 attending surgeons rated 536 categorical residents after 10,130 procedures. Performance: from the first to the last year of training, the proportion of Performance ratings for Core procedures (n = 6931) at "Practice Ready" or above increased from 12.3% to 77.1%. The predicted probability that a typical trainee would be rated as Competent after performing an average Core procedure on an average complexity patient during the last week of residency training is 90.5% (95% CI: 85.7%-94%). This falls to 84.6% for more complex patients and to less than 80% for more difficult Core procedures. Autonomy: for all procedures, the proportion of Zwisch ratings indicating meaningful autonomy ("Passive Help" or "Supervision Only") increased from 15.1% to 65.7% from the first to the last year of training. For the Core procedures performed by residents in their final 6 months of training (cholecystectomy, inguinal/femoral hernia repair, appendectomy, ventral hernia repair, and partial colectomy), the proportion of Zwisch ratings (n = 357) indicating near-independence ("Supervision Only") was 33.3%. CONCLUSIONS: US General Surgery residents are not universally ready to independently perform Core procedures by the time they complete residency training. Progressive resident autonomy is also limited. It is unknown if the amount of autonomy residents do achieve is sufficient to ensure readiness for the entire spectrum of independent practice.

Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway.

PURPOSE: The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1. METHODS: Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data. RESULTS: All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele. CONCLUSION: NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected.

Comprehensive whole-genome sequencing of an early-stage primary myelofibrosis patient defines low mutational burden and non-recurrent candidate genes.

In order to identify novel somatic mutations associated with classic BCR/ABL1-negative myeloproliferative neoplasms, we performed high-coverage genome sequencing of DNA from peripheral blood granulocytes and cultured skin fibroblasts from a patient with MPL W515K-positive primary myelofibrosis. The primary myelofibrosis genome had a low somatic mutation rate, consistent with that observed in similar hematopoietic tumor genomes. Interfacing of whole-genome DNA sequence data with RNA expression data identified three somatic mutations of potential functional significance: i) a nonsense mutation in CARD6, implicated in modulation of NF-kappaB activation; ii) a 19-base pair deletion involving a potential regulatory region in the 5'-untranslated region of BRD2, implicated in transcriptional regulation and cell cycle control; and iii) a non-synonymous point mutation in KIAA0355, an uncharacterized protein. Additional mutations in three genes (CAP2, SOX30, and MFRP) were also evident, albeit with no support for expression at the RNA level. Re-sequencing of these six genes in 178 patients with polycythemia vera, essential thrombocythemia, and myelofibrosis did not identify recurrent somatic mutations in these genes. Finally, we describe methods for reducing false-positive variant calls in the analysis of hematologic malignancies with a low somatic mutation rate. This trial is registered with ClinicalTrials.gov (NCT01108159).

Brief Report: An Evaluation of Item Bias on the Functional Activities Questionnaire.

OBJECTIVE: To evaluate whether the Functional Activities Questionnaire (FAQ), a commonly used measure of functional status in neurodegenerative disease research, performs equivalently across demographically diverse subgroups of participants. METHOD: The FAQs from 30,613 National Alzheimer's Coordinating Center participants were evaluated with a hybrid graded response model-logistic ordinal regression approach to determine the presence of differential item functioning (DIF) within five demographic groups: education, ethnicity, race, language, and sex. RESULTS: Measurable DIF was observed for FAQ items in all groups; however, measures of effect size, latent trait distributions, and item characteristic curves suggested that the impact was minimal for research and practice. CONCLUSIONS: The FAQ is able to provide minimally biased assessments of daily functioning across diverse participants, suggesting potential value for offsetting disparities in diagnosis and treatment.

Evaluating Educational Outcomes Using Patient Outcomes of New Surgeons Performing Partial Colectomy Compared to Cholecystectomy.

PURPOSE: Despite ongoing efforts to improve surgical education, surgical residents face gaps in their training. However, it is unknown if differences in the training of surgeons are reflected in the patient outcomes of those surgeons once they enter practice. This study aimed to compare the patient outcomes among new surgeons performing partial colectomy-a common procedure for which training is limited-and cholecystectomy-a common procedure for which training is robust. METHOD: The authors retrospectively analyzed all adult Medicare claims data for patients undergoing inpatient partial colectomy and inpatient cholecystectomy between 2007 and 2018. Generalized additive mixed models were used to investigate the associations between surgeon years in practice and risk-adjusted rates of 30-day serious complications and death for patients undergoing partial colectomy and cholecystectomy. RESULTS: A total of 14,449 surgeons at 4,011 hospitals performed 340,114 partial colectomy and 355,923 cholecystectomy inpatient operations during the study period. Patients undergoing a partial colectomy by a surgeon in their 1st vs 15th year of practice had higher rates of serious complications (5.22% [95% CI, 4.85%-5.60%] vs 4.37% [95% CI, 4.22%-4.52%]; P < .01) and death (3.05% [95% CI, 2.92%-3.17%] vs 2.83% [95% CI, 2.75%-2.91%]; P < .01). Patients undergoing a cholecystectomy by a surgeon in their 1st vs 15th year of practice had similar rates of 30-day serious complications (4.11% vs 3.89%; P = .11) and death (1.71% vs 1.70%; P = .93). CONCLUSIONS: Patients undergoing partial colectomy faced a higher risk of serious complications and death when the operation was performed by a new surgeon compared to an experienced surgeon. Conversely, patient outcomes following cholecystectomy were similar for new and experienced surgeons. More attention to partial colectomy during residency training may benefit patients.

Women's rape fantasies: an empirical evaluation of the major explanations.

This study evaluated explanations of rape fantasy in a sample of female undergraduates (N = 355) using a sexual fantasy checklist which included eight types of rape fantasy, participants' detailed descriptions of a rape fantasy they have had, a rape fantasy scenario audio presentation, and measures of personality. Three explanations of rape fantasy were tested: openness to sexual experience, sexual desirability, and sexual blame avoidance. Women who were higher in erotophilia and self-esteem and who had more frequent consensual sexual fantasies and more frequent desirability fantasies, particularly of performing as a stripper, had more frequent rape fantasies. Women who were higher in erotophilia, openness to fantasy, desirability fantasies, and self-esteem reported greater sexual arousal to rape fantasies. Sexual blame avoidance theory was not supported; sexual desirability theory was moderately supported; openness to sexual experience theory received the strongest support.

Representativeness of Workplace-Based Operative Performance Assessments for Resident Operative Experience.

OBJECTIVE: Workplace-based assessment is increasingly prevalent in surgical education, especially for assessing operative skill. With current implementations, not all observed clinical performances are assessed, in part because trainees often have discretion about when they seek assessment. As a result, these samples of observed operative performances may not be representative of the full breadth of experience of surgical trainees. Therefore, analyses of these samples may be biased. We aimed to benchmark patterns of procedures logged in the SIMPL operative performance assessment system against records of trainee experience in Accreditation Council for Graduate Medical Education (ACGME) case logs. DESIGN: We analyzed SIMPL longitudinal intraoperative performance assessments from categorical trainees in US general surgery residency programs. We compared overall patterns of how procedures are logged in SIMPL and in ACGME case logs using a Pearson correlation, and we examined differences in how individual procedures are logged in each system using Fisher's exact test. RESULTS: Total procedure frequency from the SIMPL dataset was strongly correlated with total procedure frequency from ACGME case logs (r = 0.86, 95% CI 0.80-0.90). A subset of these procedures (10 of 116 procedures) was logged more frequently in the SIMPL dataset. These 10 procedures accounted for 56% of SIMPL observations and 30% of ACGME logged cases. Case complexity was comparable for assessments initiated by residents and faculty. CONCLUSIONS: Samples of intraoperative performance ratings gathered using the SIMPL application largely resemble ACGME case logs. There is no evidence to indicate that residents preferentially select fewer complex cases for assessment.

Perception of sinewave vowels.

There is a significant body of research examining the intelligibility of sinusoidal replicas of natural speech. Discussion has followed about what the sinewave speech phenomenon might imply about the mechanisms underlying phonetic recognition. However, most of this work has been conducted using sentence material, making it unclear what the contributions are of listeners' use of linguistic constraints versus lower level phonetic mechanisms. This study was designed to measure vowel intelligibility using sinusoidal replicas of naturally spoken vowels. The sinusoidal signals were modeled after 300 /hVd/ syllables spoken by men, women, and children. Students enrolled in an introductory phonetics course served as listeners. Recognition rates for the sinusoidal vowels averaged 55%, which is much lower than the ∼95% intelligibility of the original signals. Attempts to improve performance using three different training methods met with modest success, with post-training recognition rates rising by ∼5-11 percentage points. Follow-up work showed that more extensive training produced further improvements, with performance leveling off at ∼73%-74%. Finally, modeling work showed that a fairly simple pattern-matching algorithm trained on naturally spoken vowels classified sinewave vowels with 78.3% accuracy, showing that the sinewave speech phenomenon does not necessarily rule out template matching as a mechanism underlying phonetic recognition.

The reliability of resident self-evaluation of operative performance.

BACKGROUND: Self-assessment is critical to professional self-regulation yet many trainees may not reliably self-evaluate. We examine the gap between resident and faculty perceptions of trainee operative performance and contributing factors. METHODS: Surgery resident and faculty evaluations of trainee performance were collected from 14 academic institutions using smartphone-based performance assessments. Differences in resident/faculty ratings evaluating the same procedure were analyzed using descriptive statistics and Bayesian mixed models. RESULTS: Of 7382 evaluations, 46% trainees and faculty performance ratings were discrepant (r = 0.47), with 80% residents rating themselves lower than faculty in those cases. This gap existed regardless of case complexity and widened as trainees gained experience. Trainees who overrated themselves had the lowest mean performance scores from faculty. CONCLUSION: Half of residents perceived their performance differently from faculty, and this difference widened for senior residents. Future focus should be to provide opportunity for trainees to improve skills to reliably assess themselves before graduation.

Mind the Gap: The Autonomy Perception Gap in the Operating Room by Surgical Residents and Faculty.

OBJECTIVE: Examine the concordance of perceived operative autonomy between attendings and resident trainees. DESIGN: Faculty and trainees rated trainee operative autonomy using the 4-level Zwisch scale over a variety of cases and training years. The respective ratings were then compared to explore the effects of experience, gender, case complexity, trainee, trainer, and other covariates to perceived autonomy. SETTING: This study was conducted over 14 general surgery programs in the United States, members of the Procedural Learning and Safety Collaborative. PARTICIPANTS: Participants included faculty and categorical trainees from 14 general surgery programs. RESULTS: A total of 8681 observations was obtained. The sample included 619 unique residents and 457 different attendings. A total of 598 distinct procedures was performed. In 60% of the cases, the autonomy ratings between trainees and attendings were concordant, with only 3.5% of cases discrepant by more than 1 level. An autonomy perception gap was modeled based on the discrepancy between the trainee and attending Zwisch ratings for the same case. The mean Zwisch score expected for a trainee was lower than the attending across all scenarios. Trainees were more likely to perceive relatively more autonomy in the second half of the year. The autonomy perception gap decreased with increasing case complexity. As trainees gained experience, the perception gap increased with trainees underestimating autonomy. CONCLUSIONS: Trainees and attendings generally demonstrated concordance on autonomy perception scores. However, in 40% of cases, a perception gap exists between trainee and attending with the trainee generally underestimating autonomy. The gap worsens as the trainee progresses through residency. This perception gap suggests that attendings and trainees could be better aligned on teaching goals and expectations.

Concordance Between Expert and Nonexpert Ratings of Condensed Video-Based Trainee Operative Performance Assessment.

OBJECTIVE: We examined the impact of video editing and rater expertise in surgical resident evaluation on operative performance ratings of surgical trainees. DESIGN: Randomized independent review of intraoperative video. SETTING: Operative video was captured at a single, tertiary hospital in Boston, MA. PARTICIPANTS: Six common general surgery procedures were video recorded of 6 attending-trainee dyads. Full-length and condensed versions (n = 12 videos) were then reviewed by 13 independent surgeon raters (5 evaluation experts, 8 nonexperts) using a crossed design. Trainee performance was rated using the Operative Performance Rating Scale, System for Improving and Measuring Procedural Learning (SIMPL) Performance scale, the Zwisch scale, and ten Cate scale. These ratings were then standardized before being compared using Bayesian mixed models with raters and videos treated as random effects. RESULTS: Editing had no effect on the Operative Performance Rating Scale Overall Performance (-0.10, p = 0.30), SIMPL Performance (0.13, p = 0.71), Zwisch (-0.12, p = 0.27), and ten Cate scale (-0.13, p = 0.29). Additionally, rater expertise (evaluation expert vs. nonexpert) had no effect on the same scales (-0.16 (p = 0.32), 0.18 (p = 0.74), 0.25 (p = 0.81), and 0.25 (p = 0.17). CONCLUSIONS: There is little difference in operative performance assessment scores when raters use condensed videos or when raters who are not experts in surgical resident evaluation are used. Future validation studies of operative performance assessment scales may be facilitated by using nonexpert surgeon raters viewing videos condensed using a standardized protocol.

Do End-of-Rotation Evaluations Adequately Assess Readiness to Operate?

PURPOSE: Medical educators have developed no standard way to assess the operative performance of surgical residents. Most residency programs use end-of-rotation (EOR) evaluations for this purpose. Recently, some programs have implemented workplace-based "microassessment" tools that faculty use to immediately rate observed operative performance. The authors sought to determine (1) the degree to which EOR evaluations correspond to workplace-based microassessments and (2) which factors most influence EOR evaluations and directly observed workplace-based performance ratings and how the influence of those factors differs for each assessment method. METHOD: In 2017, the authors retrospectively analyzed EOR evaluations and immediate postoperative assessment ratings of surgical trainees from a university-based training program from the 2015-2016 academic year. A Bayesian multivariate mixed model was constructed to predict operative performance ratings for each type of assessment. RESULTS: Ratings of operative performance from EOR evaluations vs workplace-based microassessment ratings had a Pearson correlation of 0.55. Postgraduate year (PGY) of training was the most important predictor of operative performance ratings on EOR evaluations: Model estimates ranged from 0.62 to 1.75 and increased with PGY. For workplace-based assessment, operative autonomy rating was the most important predictor of operative performance (coefficient = 0.74). CONCLUSIONS: EOR evaluations are perhaps most useful in assessing the ability of a resident to become a surgeon compared with other trainees in the same PGY of training. Workplace-based microassessments may be better for assessing a trainee's ability to perform specific procedures autonomously, thus perhaps providing more insight into a trainee's true readiness for operative independence.

High-density lipoprotein modulates oxidized phospholipid signaling in human endothelial cells from proinflammatory to anti-inflammatory.

OBJECTIVE: Oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycero-phosphorylcholine (Ox-PAPC) and its component phospholipid, 1-palmitoyl-2-(5,6 epoxyisoprostanoyl)-sn-glycero-3-phosphocholine (PEIPC), which are present in atherosclerotic lesions, activate endothelial cells to induce a complex inflammatory and pro-oxidant response. Previously, we demonstrated induction of genes regulating chemotaxis, sterol biosynthesis, the unfolded protein response, and redox homeostasis by Ox-PAPC in human aortic endothelial cells (HAECs). Activation of the c-Src kinase/signal transducer and activator of transcription 3 and the endothelial nitric oxide synthase/sterol regulatory element binding protein (SREBP) pathways were shown to regulate several of these inflammatory effects of Ox-PAPC in HAECs. The goal of the current studies was to determine the role of high-density lipoprotein (HDL) in regulating Ox-PAPC signaling in HAECs. METHODS AND RESULTS: Using quantitative real-time polymerase chain reaction, Western analysis, and functional studies, we demonstrated that pretreatment of HAECs with HDL reduced the induction of inflammatory, sterol biosynthetic, and unfolded protein response genes by Ox-PAPC and PEIPC; Ox-PAPC-induced chemotactic activity and monocyte binding were also decreased. These effects were associated with HDL inhibition of Ox-PAPC-induced c-Src, signal transducer and activator of transcription 3, and SREBP activation, alterations in endothelial nitric oxide synthase phosphorylation (previously associated with the inflammatory action of Ox-PAPC), and a decrease in superoxide formation. Finally, we demonstrated that treatment with HDL did not inhibit Ox-PAPC and PEIPC-induced activation of redox pathways, which protect the cell from the effects of oxidative stress. CONCLUSIONS: Taken together, these studies demonstrated that HDL inhibits the pro-inflammatory effects of Ox-PAPC and PEIPC, while maintaining the antioxidant activities of these lipids.

A Randomized Controlled Trial of Balloon Dilation as a Treatment for Persistent Eustachian Tube Dysfunction With 1-Year Follow-Up.

OBJECTIVE: Compare Eustachian tube balloon dilation versus continued medical therapy (control) for treating persistent Eustachian tube dysfunction (ETD). STUDY DESIGN: Prospective, multicenter, randomized controlled trial. SETTING: Tertiary care academic center and private practice. PATIENTS: Diagnosed with medically refractory persistent ETD. INTERVENTIONS: 1:1 Randomization to balloon dilation or control. After 6 weeks, control participants had the option to undergo balloon dilation if symptoms persisted. MAIN OUTCOME MEASURES: Primary efficacy endpoint was the comparison between treatment arms in the mean change from baseline in the 7-item Eustachian Tube Dysfunction Questionnaire (ETDQ-7) score. Primary safety endpoint was complication rate. RESULTS: Sixty participants were randomized (31 balloon dilation, 29 control). Mean (SD) change in overall ETDQ-7 score at 6 weeks was -2.9 (1.4) for balloon dilation compared with -0.6 (1.0) for control: balloon dilation was superior to control (p < 0.0001). No complications were reported in either study arm. Among participants with abnormal baseline assessments, improvements in tympanogram type (p < 0.006) and tympanic membrane position (p < 0.001) were significantly better for balloon dilation than control. Technical success was 100% (91 successful dilations/91 attempts) and most procedures (72%) were completed in the office under local anesthesia. Improvements in the ETDQ-7 scores were maintained through 12 months after balloon dilation. CONCLUSIONS: Balloon dilation is a safe and effective treatment for persistent ETD. Based on improved ETDQ-7 scores, balloon dilation is superior to continued medical management for persistent ETD. Symptom improvement is durable through a minimum of 12 months. Procedures are well tolerated in the office setting under local anesthesia.

The unfolded protein response is an important regulator of inflammatory genes in endothelial cells.

OBJECTIVE: Oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycero-phosphorylcholine (oxPAPC) accumulates in atherosclerotic lesions and in vitro studies suggest that it mediates chronic inflammatory response in endothelial cells (ECs). The goal of our studies was to identify pathways mediating the induction of inflammatory genes by oxPAPC. METHODS AND RESULTS: Using expression arrays, quantitative polymerase chain reaction (PCR), and immunoblotting we demonstrate that oxPAPC leads to endoplasmic reticulum stress and activation of the unfolded protein response (UPR) in human aortic ECs. Immunohistochemistry analysis of human atherosclerotic lesions indicated that UPR is induced in areas containing oxidized phospholipids. Using the UPR inducing agent tunicamycin and selective siRNA targeting of the ATF4 and XBP1 branches of the UPR, we demonstrate that these transcription factors are essential mediators of IL8, IL6, and MCP1 expression in human aortic ECs required for maximal inflammatory gene expression in the basal state and after oxPAPC treatment. We also identify a novel oxPAPC-induced chemokine, the CXC motif ligand 3 (CXCL3), and show that its expression requires XBP1. CONCLUSIONS: These data suggest that the UPR pathway is a general mediator of vascular inflammation and EC dysfunction in atherosclerosis, and, likely, other inflammatory disorders.

De Novo Occurrence of a Variant in ARL3 and Apparent Autosomal Dominant Transmission of Retinitis Pigmentosa.

BACKGROUND: Retinitis pigmentosa is a phenotype with diverse genetic causes. Due to this genetic heterogeneity, genome-wide identification and analysis of protein-altering DNA variants by exome sequencing is a powerful tool for novel variant and disease gene discovery. In this study, exome sequencing analysis was used to search for potentially causal DNA variants in a two-generation pedigree with apparent dominant retinitis pigmentosa. METHODS: Variant identification and analysis of three affected members (mother and two affected offspring) was performed via exome sequencing. Parental samples of the index case were used to establish inheritance. Follow-up testing of 94 additional retinitis pigmentosa pedigrees was performed via retrospective analysis or Sanger sequencing. RESULTS AND CONCLUSIONS: A total of 136 high quality coding variants in 123 genes were identified which are consistent with autosomal dominant disease. Of these, one of the strongest genetic and functional candidates is a c.269A>G (p.Tyr90Cys) variant in ARL3. Follow-up testing established that this variant occurred de novo in the index case. No additional putative causal variants in ARL3 were identified in the follow-up cohort, suggesting that if ARL3 variants can cause adRP it is an extremely rare phenomenon.

Phonetics exercises using the Alvin experiment-control software.

PURPOSE: Exercises are described that were designed to provide practice in phonetic transcription for students taking an introductory phonetics course. The goal was to allow instructors to offload much of the drill that would otherwise need to be covered in class or handled with paper-and-pencil tasks using text rather than speech as input. METHOD: The exercises were developed using Alvin, a general-purpose software package for experiment design and control. The simplest exercises help students learn sound-symbol associations. For example, a vowel-transcription exercise presents listeners with consonant-vowel-consonant syllables on each trial; students are asked to choose among buttons labeled with phonetic symbols for 12 vowels. Several word-transcription exercises are included in which students hear a word and are asked to enter a phonetic transcription. Immediate feedback is provided for all of the exercises. An explanation of the methods that are used to create exercises is provided. RESULTS: Although no formal evaluation was conducted, comments on course evaluations suggest that most students found the exercises to be useful. CONCLUSIONS: Exercises were developed for use in an introductory phonetics course. The exercises can be used in their current form, they can be modified to suit individual needs, or new exercises can be developed.