Real-world effectiveness and satisfaction with intravenous eptinezumab treatment in patients with chronic migraine: REVIEW, an observational, multi-site, US-based study.

BACKGROUND: Despite recent advancements in migraine treatment, some patients continue to endure significant disease burden. Due to the controlled nature of randomized trials in migraine prevention, many real-world patients with comorbidities or prior exposure to certain therapies are excluded. Capturing evidence of the effectiveness of treatment in real-world clinical settings can further shape treatment paradigms. The objective of this study was to develop a comprehensive understanding of both patients' and physicians' real-world experiences with eptinezumab for chronic migraine (CM). METHODS: REVIEW (Real-world EVidence and Insights into Experiences With eptinezumab) is an observational, multi-site (n = 4), US-based study designed to evaluate real-world experiences of patients treated with eptinezumab and their treating physicians. Patients were ≥ 18 years of age, with a diagnosis of CM, who had completed ≥ 2 consecutive eptinezumab infusion cycles (≥ 6 months of exposure). The study included a retrospective chart review, a patient survey, and a semi-structured physician interview that assessed patient and/or physician satisfaction with elements of daily living / well-being, migraine symptomology, and perspectives of the eptinezumab infusion experience. RESULTS: Of the 94 patients enrolled, 83% (78/94) were female, the mean age was 49.2 years, and the mean time since migraine diagnosis was 15.4 years. Before eptinezumab treatment, patients experienced a mean of 8 self-reported "good" days/month, which increased to 18 after treatment. Most patients took, on average, ≥ 10 days/month of prescription and/or over-the-counter medication (81% [75/93] and 66% [61/93], respectively) to treat migraine attacks before eptinezumab treatment, which dropped to 26% (24/93) and 23% (21/93) following eptinezumab treatment. Prior to receiving eptinezumab, 62% (58/93) of patients indicated being at least slightly concerned about infusions; after eptinezumab infusion, this dropped to 14% (13/93). These patient survey findings were consistent with physician responses. CONCLUSION: This real-world evidence study demonstrated high overall satisfaction with the effectiveness of eptinezumab treatment for CM among most patients and their physicians.

Quality-Based Evaluation of Patient-Facing Online Education Materials Regarding Facial Filler Procedures.

Injectable facial fillers have become tremendously more popular in recent years, and the Internet offers a proportional amount of consumer-facing educational material. This study sought to explore the quality of these online materials. The top 20 Web sites offering educational materials about facial filler were identified via Google search and sorted by source: Medical Professional Boards, Hospitals and Providers, Medical News and Reference, and Fashion. The materials were assessed for overall quality with the validated DISCERN instrument. The authors also assessed understandability and actionability (Patient Education Material Assessment Tool - PEMAT), accuracy, comprehensiveness, and readability (Flesch-Kincaid Grade Level and Flesch Reading Ease). The mean DISCERN score was 46.9 ± 7.6, which is considered "fair" quality educational material; above "poor," but below "good" and "excellent." Understandability and actionability scores were low, particularly with respect to visual aids. The materials were generally accurate (76-99%), but scored poorly in comprehensiveness, as 15% failed to mention any risks/adverse effects and only 35% mentioned cost. On average, readability was at an 11th grade level, far more complex than ideal (< 6th grade level). Information disseminated from seemingly reputable sources such as professional boards and hospitals/providers were not of higher quality or superior in any of the above studied domains. In conclusion, online educational materials related to injectable facial fillers are of subpar quality, including those from academic and professional organizations. Visual aids were particularly weak. The facial rejuvenation community should make a concerted effort to set a higher standard for disseminating such information.

Investigating SH-SY5Y Neuroblastoma Cell Surfaceome as a Model for Neuronal-Targeted Novel Therapeutic Modalities.

The SH-SY5Y neuroblastoma cells are a widely used in vitro model approximating neurons for testing the target engagement of therapeutics designed for neurodegenerative diseases and pain disorders. However, their potential as a model for receptor-mediated delivery and uptake of novel modalities, such as antibody-drug conjugates, remains understudied. Investigation of the SH-SY5Y cell surfaceome will aid in greater in vitro to in vivo correlation of delivery and uptake, thereby accelerating drug discovery. So far, the majority of studies have focused on total cell proteomics from undifferentiated and differentiated SH-SY5Y cells. While some studies have investigated the expression of specific proteins in neuroblastoma tissue, a global approach for comparison of neuroblastoma cell surfaceome to the brain and dorsal root ganglion (DRG) neurons remains uninvestigated. Furthermore, an isoform-specific evaluation of cell surface proteins expressed on neuroblastoma cells remains unexplored. In this study, we define a bioinformatic workflow for the identification of high-confidence surface proteins expressed on brain and DRG neurons using tissue proteomic and transcriptomic data. We then delineate the SH-SY5Y cell surfaceome by surface proteomics and show that it significantly overlaps with the human brain and DRG neuronal surface proteome. We find that, for 32% of common surface proteins, SH-SY5Y-specific major isoforms are alternatively spliced, maintaining their protein-coding ability, and are predicted to localize to the cell surface. Validation of these isoforms using surface proteomics confirms a SH-SY5Y-specific alternative NRCAM (neuron-glia related cell adhesion molecule) isoform, which is absent in typical brain neurons, but present in neuroblastomas, making it a receptor of interest for neuroblastoma-specific therapeutics.

Beauty is in the eye of the follower: Facial aesthetics in the age of social media.

BACKGROUND: The advent of social media has influenced the relationship between aesthetic surgeons and their patients, as well as the motivations of such patients to seek cosmetic surgery. AIMS & OBJECTIVES: To determine how the cephalometric proportions of modern social media models fit with historical canons of beauty. MATERIALS & METHODS: Frontal and lateral photographs of 20 high-influence female Instagram models were obtained and evaluated for cephalometric measures. The means of these measures were compared with previous reports in the literature. RESULTS: Cephalometric measurements of social media models were in agreement with historical ideals of beauty for Nostril axis (120.7°), Goode's ratio (0.6), Nasofacial angle (35.7°), Nasofrontal angle (130.9°), and the horizontal thirds. Results were discrepant from historical ideals for the Nasolabial angle (82.6°) and the vertical facial fifths. CONCLUSION: Cephalometric measurements of social media models in the digital age closely resemble the ideal values proposed by previous authors. Due to a preference for larger or altered lip profiles, nostril axis is a more reliable measure of nasal tip rotation than nasolabial angle.

Sexual Dimorphism of the Nasal Skin and Soft Tissue Envelope.

Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Setbacks in Forehead Feminization Cranioplasty: A Systematic Review of Complications and Patient-Reported Outcomes.

IMPORTANCE: Forehead feminization cranioplasty (FFC) is an important component of gender-affirming surgery and has become increasingly popular in recent years. Little objective evidence exists for the procedure's safety and clinical impact via patient-reported outcome measures (PROMs). OBJECTIVE: To determine what complications are observed following FFC, the relative frequency of complications by surgical technique, and what impact the procedure has on patient's quality of life. DATA SOURCES: Database searches were performed in PubMed/MEDLINE, Scopus, CINAHL, Cochrane CENTRAL, Cochrane Database of Systematic Reviews, and PsycINFO. The search terms included variations of forehead setback/FFC. Both controlled vocabularies (i.e., MeSH and CINAHL's Suggested Subject Terms) and keywords in the title or abstract fields were searched. STUDY SELECTION: Two independent reviewers screened the titles and abstracts of all articles. Two independent surgeon reviewers evaluated the full text of all included articles, and relevant data points were extracted. MAIN OUTCOMES AND MEASURES: Complications and complication rate observed following FFC. Additional outcome measures were the approach utilized, concurrent procedures performed, and the use and findings of a PROM. RESULTS: Ten articles describing FFC were included, encompassing 673 patients. The overall pooled complication rate was 1.3%. PROMs were used in half of studies, with no standardization among studies. CONCLUSIONS AND RELEVANCE: Complications following FFC are rare and infrequently require reoperation. Further studies into standardized and validated PROMs in facial feminization patients are warranted. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

The Selfie View: Perioperative Photography in the Digital Age.

BACKGROUND: The aesthetics of social media have become increasingly important to cosmetic surgery patients in recent years; however, aesthetic treatments have not kept pace with the desires of modern patients. The current study investigates the most common angles employed by various user cohorts when posting a selfie on social media platforms and proposes that aesthetic surgeons consider utilizing a selfie angle alongside standard pre- and postoperative photographic views. METHODS: Full face photographs published on the social media platform Instagram™ with the tag #selfie were divided into three cohorts: female models/influencers, amateur females, and amateur males. Each cohort contained 100 photographs. The photographs were analyzed using cloud-based facial analysis software for facial pan, roll, and tilt relative to the camera. RESULTS: One hundred photographs from each cohort were analyzed and demonstrated that amateur females (AF) take photographs from higher angles than amateur males (AM) or model females (MF). Roll-off-midline was significantly greater for AF and MF as compared to AM. The MF group had significantly a greater pan-off-midline as compared to AF and AM, while AF had significantly a greater pan-off-midline than AM. CONCLUSIONS: Common photography practices employed within selfie photographs utilize angles not captured in standard perioperative photographs. This study supports the implementation of a selfie photograph into the standard set of pre- and postoperative photographs taken by aesthetic surgeons to evaluate the effects of interventions in the context of selfie photography. The angle employed can vary depending upon the demographic profile of the patient. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Level of Evidence in Facial Plastic Surgery Research: A Procedure-Level Analysis.

BACKGROUND: As evidence-based medicine has taken hold across medical specialties, the level of evidence within the facial plastic surgery literature has risen, but remains weak in comparison. There has not yet been a systematic, critical appraisal of the relative strength of evidence among subsets of the practice of facial plastic surgery. METHODS: The current study is a systematic review, designed to evaluate the level of evidence observed in the facial plastic surgery literature. Five journals were queried using facial plastic surgery terms for four selected years over a 10-year period. Following screening, articles were assigned to a category regarding subject matter, assessed for the presence of various methodological traits, and evaluated for overall level of evidence. Comparisons were made in regard to level of evidence across the breadth of facial plastic surgery subject matter. RESULTS: A total of 826 articles were included for final review. Studies on operative facial rejuvenation and rhinoplasty had significantly fewer authors on average than studies on cancer reconstruction or craniofacial topics. Craniofacial studies demonstrated higher levels of evidence relative to all other categories, with the exception of facial paralysis and facial trauma studies, from which there was no significant difference. In general, reconstructive studies had significantly more authors and higher levels of evidence than did articles with an aesthetic focus. CONCLUSION: Level of evidence in facial plastic surgery remains relatively weak overall. Reconstructive and particularly craniofacial studies demonstrate higher mean level of evidence, relative to other subsets of facial plastic surgery. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Influence of Serotonin Transporter SLC6A4 Genotype on the Effect of Psychosocial Stress on Cognitive Performance: An Exploratory Pilot Study.

BACKGROUND AND OBJECTIVE: Previous research has shown an effect of various psychosocial stressors on unconstrained cognitive flexibility, such as searching through a large set of potential solutions in the lexical-semantic network during verbal problem-solving. Functional magnetic resonance imaging has shown that the presence of the short (S) allele (lacking a 43-base pair repeat) of the promoter region of the gene (SLC6A4) encoding the serotonin transporter (5-HTT) protein is associated with a greater amygdalar response to emotional stimuli and a greater response to stressors. Therefore, we hypothesized that the presence of the S-allele is associated with greater stress-associated impairment in performance on an unconstrained cognitive flexibility task, anagrams. METHODS: In this exploratory pilot study, 28 healthy young adults were genotyped for long (L)-allele versus S-allele promoter region polymorphism of the 5-HTT gene, SLC6A4. Participants solved anagrams during the Trier Social Stress Test, which included public speaking and mental arithmetic stressors. We compared the participants' cognitive response to stress across genotypes. RESULTS: A Gene×Stress interaction effect was observed in this small sample. Comparisons revealed that participants with at least one S-allele performed worse during the Stress condition. CONCLUSIONS: Genetic susceptibility to stress conferred by SLC6A4 appeared to modulate unconstrained cognitive flexibility during psychosocial stress in this exploratory sample. If confirmed, this finding may have implications for conditions associated with increased stress response, including performance anxiety and cocaine withdrawal. Future work is needed both to confirm our findings with a larger sample and to explore the mechanisms of this proposed effect.

Considerations for Temporomandibular Joint Procurement in Vascularized Composite Allotransplantation.

Methods for harvest of the temporomandibular joint (TMJ) for transplantation may involve several anatomic levels. The authors aim to assess the feasibility and identify challenges with 2 such methods, resuspending the donor condyles from the recipient glenoid fossae and en bloc harvest of the joint and surrounding temporal bone with plate-fixation to the recipient skull base. Two mock face transplantations were carried out using 4 fresh cadavers. Computed tomography imaging was obtained before and after the procedures to assess the technical success of each method. Both techniques were technically successful, allowing for full passive jaw range of motion following graft transfer and appropriate condyle positioning as assessed by computed tomography. En bloc TMJ harvest allowed for transfer of the entire joint without violating its capsule or altering its biomechanics. The authors found this technique better able to avoid issues with size mismatch between the donor mandible and recipient skull base width. When no such mismatch exists, graft harvest at the level of the mandibular condyle is technically easier and less time consuming. Although both methods of TMJ harvest are technically feasible with acceptable immediate postoperative jaw position and range of motion, the en bloc technique allows for more natural jaw function with less risk of postoperative joint immobility by preserving the joint capsule and its ligamentous support.

Genomic structure and expression of the human serotonin 2A receptor gene (HTR2A) locus: identification of novel HTR2A and antisense (HTR2A-AS1) exons.

BACKGROUND: The serotonin 2A receptor is widely implicated in genetic association studies and remains an important drug target for psychiatric, neurological, and cardiovascular conditions. RNA sequencing redefined the architecture of the serotonin 2A receptor gene (HTR2A), revealing novel mRNA transcript isoforms utilizing unannotated untranslated regions of the gene. Expression of these untranslated regions is modulated by common single nucleotide polymorphisms (SNPs), namely rs6311. Previous studies did not fully capture the complexity of the sense- and antisense-encoded transcripts with respect to novel exons in the HTR2A gene locus. Here, we comprehensively catalogued exons and RNA isoforms for both HTR2A and HTR2A-AS1 using RNA-Seq from human prefrontal cortex and multiple mouse tissues. We subsequently tested associations between expression of newfound gene features and common SNPs in humans. RESULTS: We find that the human HTR2A gene spans ~66 kilobases and consists of 7, rather than 4 exons. Furthermore, the revised human HTR2A-AS1 gene spans ~474 kilobases and consists of 18, rather than 3 exons. Three HTR2A exons directly overlap with HTR2A-AS1 exons, suggesting potential for complementary nucleotide interactions. The repertoire of possible mouse Htr2a splice isoforms is remarkably similar to humans and we also find evidence for overlapping sense-antisense transcripts in the same relative positions as the human transcripts. rs6311 and SNPs in high linkage disequilibrium are associated with HTR2A-AS1 expression, in addition to previously described associations with expression of the extended 5' untranslated region of HTR2A. CONCLUSIONS: Our proposed HTR2A and HTR2A-AS1 gene structures dramatically differ from current annotations, now including overlapping exons on the sense and anti-sense strands. We also find orthologous transcript isoforms expressed in mice, providing opportunities to elucidate the biological roles of the human isoforms using a model system. Associations between rs6311 and expression of HTR2A and HTR2A-AS1 suggest this polymorphism is capable of modulating the expression of the sense or antisense transcripts. Still unclear is whether these SNPs act directly on the expression of the sense or antisense transcripts and whether overlapping exons are capable of interacting through complimentary base-pairing. Additional studies are necessary to determine the extent and nature of interactions between the SNPs and the transcripts prior to interpreting these findings in the context of phenotypes associated with HTR2A.

Analyzing allele specific RNA expression using mixture models.

BACKGROUND: Measuring allele-specific RNA expression provides valuable insights into cis-acting genetic and epigenetic regulation of gene expression. Widespread adoption of high-throughput sequencing technologies for studying RNA expression (RNA-Seq) permits measurement of allelic RNA expression imbalance (AEI) at heterozygous single nucleotide polymorphisms (SNPs) across the entire transcriptome, and this approach has become especially popular with the emergence of large databases, such as GTEx. However, the existing binomial-type methods used to model allelic expression from RNA-seq assume a strong negative correlation between reference and variant allele reads, which may not be reasonable biologically. RESULTS: Here we propose a new strategy for AEI analysis using RNA-seq data. Under the null hypothesis of no AEI, a group of SNPs (possibly across multiple genes) is considered comparable if their respective total sums of the allelic reads are of similar magnitude. Within each group of "comparable" SNPs, we identify SNPs with AEI signal by fitting a mixture of folded Skellam distributions to the absolute values of read differences. By applying this methodology to RNA-Seq data from human autopsy brain tissues, we identified numerous instances of moderate to strong imbalanced allelic RNA expression at heterozygous SNPs. Findings with SLC1A3 mRNA exhibiting known expression differences are discussed as examples. CONCLUSION: The folded Skellam mixture model searches for SNPs with significant difference between reference and variant allele reads (adjusted for different library sizes), using information from a group of "comparable" SNPs across multiple genes. This model is particularly suitable for performing AEI analysis on genes with few heterozygous SNPs available from RNA-seq, and it can fit over-dispersed read counts without specifying the direction of the correlation between reference and variant alleles.

Conditional entropy in variation-adjusted windows detects selection signatures associated with expression quantitative trait loci (eQTLs).

BACKGROUND: Over the past 50,000 years, shifts in human-environmental or human-human interactions shaped genetic differences within and among human populations, including variants under positive selection. Shaped by environmental factors, such variants influence the genetics of modern health, disease, and treatment outcome. Because evolutionary processes tend to act on gene regulation, we test whether regulatory variants are under positive selection. We introduce a new approach to enhance detection of genetic markers undergoing positive selection, using conditional entropy to capture recent local selection signals. RESULTS: We use conditional logistic regression to compare our Adjusted Haplotype Conditional Entropy (H|H) measure of positive selection to existing positive selection measures. H|H and existing measures were applied to published regulatory variants acting in cis (cis-eQTLs), with conditional logistic regression testing whether regulatory variants undergo stronger positive selection than the surrounding gene. These cis-eQTLs were drawn from six independent studies of genotype and RNA expression. The conditional logistic regression shows that, overall, H|H is substantially more powerful than existing positive-selection methods in identifying cis-eQTLs against other Single Nucleotide Polymorphisms (SNPs) in the same genes. When broken down by Gene Ontology, H|H predictions are particularly strong in some biological process categories, where regulatory variants are under strong positive selection compared to the bulk of the gene, distinct from those GO categories under overall positive selection. . However, cis-eQTLs in a second group of genes lack positive selection signatures detectable by H|H, consistent with ancient short haplotypes compared to the surrounding gene (for example, in innate immunity GO:0042742); under such other modes of selection, H|H would not be expected to be a strong predictor.. These conditional logistic regression models are adjusted for Minor allele frequency(MAF); otherwise, ascertainment bias is a huge factor in all eQTL data sets. Relationships between Gene Ontology categories, positive selection and eQTL specificity were replicated with H|H in a single larger data set. Our measure, Adjusted Haplotype Conditional Entropy (H|H), was essential in generating all of the results above because it: 1) is a stronger overall predictor for eQTLs than comparable existing approaches, and 2) shows low sequential auto-correlation, overcoming problems with convergence of these conditional regression statistical models. CONCLUSIONS: Our new method, H|H, provides a consistently more robust signal associated with cis-eQTLs compared to existing methods. We interpret this to indicate that some cis-eQTLs are under positive selection compared to their surrounding genes. Conditional entropy indicative of a selective sweep is an especially strong predictor of eQTLs for genes in several biological processes of medical interest. Where conditional entropy is a weak or negative predictor of eQTLs, such as innate immune genes, this would be consistent with balancing selection acting on such eQTLs over long time periods. Different measures of selection may be needed for variant prioritization under other modes of evolutionary selection.

Selectivity of Terahertz Gas-Phase Spectroscopy.

Analytical potential of terahertz (THz) spectroscopy is assessed by comparing selectivity for a set of eight environmentally important gases over THz and infrared (IR) optical frequencies. Selectivity coefficients are determined over selected spectral regions for acetaldehyde, acetonitrile, ethanol, water, methanol, ammonia, propionaldehyde, and propionitrile. These selectivity coefficients quantify the magnitude of the net analyte signal for each test compound relative to the other seven. In addition to the THz spectral range (2-125 cm(-1)), selectivity coefficients are determined for the following IR regions 600-1300, 1300-2000, 2600-3100, 3100-4000, and 4000-6500 cm(-1). Highest selectivity is afforded over the THz frequencies for six of the eight test compounds and THz selectivity coefficients for the other two gases (water and acetonitrile) are acceptable for environmental measurements.

Numb Chin Syndrome.

"Numb chin syndrome" (NCS) refers to new-onset numbness of the lower lip and chin within the distribution of the mental or inferior alveolar nerves. While this focal numbness may be downplayed or even overlooked by patients and clinicians, in the right clinical scenario this may be the presenting symptom of an underlying malignancy. In the absence of any obvious, temporally related dental cause, there are certain conditions that clinicians should consider including orofacial and systemic malignancies as well as several inflammatory disorders. Thorough diagnostic evaluation should always be performed when no clear cause is evident. This paper will discuss the differential, recommended evaluations, and the prognosis, for a patient presenting with NCS.

Serotonin 2A receptor gene (HTR2A) regulatory variants: possible association with severity of depression symptoms in children with autism spectrum disorder.

OBJECTIVE AND BACKGROUND: Our aim was to characterize the association of 2 functional single nucleotide polymorphisms (rs6311 and rs6314) in the serotonin 2A receptor gene (HTR2A) with severity of depression symptoms in children with autism spectrum disorder. These polymorphisms have been shown to be associated with depression symptom severity and response to selective serotonin reuptake inhibitor drugs in adults with diagnosed depressive disorder. METHODS: Parents of 104 children with autism spectrum disorder rated their children's depressive symptoms using a validated scale based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. We compared severity of depression symptoms across the rs6311 and rs6314 genotypes, measured from the children's genomic DNA. RESULTS: Children homozygous for the G allele of rs6311 had significantly more severe depression symptoms than those with G/A or A/A genotypes (P=0.025). The effect size (partial eta-squared) was small (ηp=0.047) but was somewhat larger when we controlled for severity of generalized anxiety disorder symptoms (P=0.006, ηp=0.072). When we restricted our analyses to white participants, our results were essentially the same as for the entire sample (P=0.004, ηp=0.086). There was no significant association between rs6314 (C/C versus T carriers) and severity of depression. CONCLUSIONS: Our findings suggest that the HTR2A functional rs6311 polymorphism, which other studies have associated with differential HTR2A mRNA expression, may modulate the severity of depression symptoms in children with autism spectrum disorder. These tentative, hypothesis-generating findings need replication with larger, independent samples.

Whole transcriptome RNA-Seq allelic expression in human brain.

BACKGROUND: Measuring allelic RNA expression ratios is a powerful approach for detecting cis-acting regulatory variants, RNA editing, loss of heterozygosity in cancer, copy number variation, and allele-specific epigenetic gene silencing. Whole transcriptome RNA sequencing (RNA-Seq) has emerged as a genome-wide tool for identifying allelic expression imbalance (AEI), but numerous factors bias allelic RNA ratio measurements. Here, we compare RNA-Seq allelic ratios measured in nine different human brain regions with a highly sensitive and accurate SNaPshot measure of allelic RNA ratios, identifying factors affecting reliable allelic ratio measurement. Accounting for these factors, we subsequently surveyed the variability of RNA editing across brain regions and across individuals. RESULTS: We find that RNA-Seq allelic ratios from standard alignment methods correlate poorly with SNaPshot, but applying alternative alignment strategies and correcting for observed biases significantly improves correlations. Deploying these methods on a transcriptome-wide basis in nine brain regions from a single individual, we identified genes with AEI across all regions (SLC1A3, NHP2L1) and many others with region-specific AEI. In dorsolateral prefrontal cortex (DLPFC) tissues from 14 individuals, we found evidence for frequent regulatory variants affecting RNA expression in tens to hundreds of genes, depending on stringency for assigning AEI. Further, we find that the extent and variability of RNA editing is similar across brain regions and across individuals. CONCLUSIONS: These results identify critical factors affecting allelic ratios measured by RNA-Seq and provide a foundation for using this technology to screen allelic RNA expression on a transcriptome-wide basis. Using this technology as a screening tool reveals tens to hundreds of genes harboring frequent functional variants affecting RNA expression in the human brain. With respect to RNA editing, the similarities within and between individuals leads us to conclude that this post-transcriptional process is under heavy regulatory influence to maintain an optimal degree of editing for normal biological function.

Variants of DENND1B associated with asthma in children.

BACKGROUND: Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown. METHODS: We carried out a genomewide association study involving children with asthma. The sample included 793 North American children of European ancestry with persistent asthma who required daily inhaled glucocorticoid therapy and 1988 matched controls (the discovery set). We also tested for genomewide association in an independent cohort of 917 persons of European ancestry who had asthma and 1546 matched controls (the replication set). Finally, we tested for an association between 20 single-nucleotide polymorphisms (SNPs) at chromosome 1q31 and asthma in 1667 North American children of African ancestry who had asthma and 2045 ancestrally matched controls. RESULTS: In our meta-analysis of all samples from persons of European ancestry, we observed an association, with genomewide significance, between asthma and SNPs at the previously reported locus on 17q21 and an additional eight SNPs at a novel locus on 1q31. The SNP most strongly associated with asthma was rs2786098 (P=8.55x10(-9)). We observed replication of the association of asthma with SNP rs2786098 in the independent series of persons of European ancestry (combined P=9.3x10(-11)). The alternative allele of each of the eight SNPs on chromosome 1q31 was strongly associated with asthma in the children of African ancestry (P=1.6x10(-13) for the comparison across all samples). The 1q31 locus contains the 1q31 locus contains DENND1B, a gene expressed by natural killer cells and dendritic cells. DENND1B protein is predicted to interact with the tumor necrosis factor α receptor [corrected]. CONCLUSIONS: We have identified a locus containing DENND1B on chromosome 1q31.3 that is associated with susceptibility to asthma.

A Pilot Study of Symptoms of Major Depressive Disorder in Medical Students at an Osteopathic Medical School Before and After High-Stakes Examinations.

Background: Given the high prevalence of symptoms of major depressive disorder (MDD) in medical students, identifying factors that impact the development of such symptoms is important. Previous data suggest that medical students can experience symptoms of MDD after medical school exams. It is not known if medical students experience more symptoms of MDD directly before or after exams. The aim of the current study is to determine the prevalence of symptoms of MDD in first- and second-year medical students directly before and after high-stakes medical school examinations. Methods: Two anonymous surveys were sent via REDCap to first- and second-year medical students at the University of New England College of Osteopathic Medicine. A pre-exam survey on the day of the exam asking about the past three days' MDD symptoms, and a post-exam survey sent three days after the exam asking about MDD symptoms experienced after the exam was sent out to a total of 391 students with a response rate of 23%. Results: First- and second-year medical students regardless of gender experienced symptoms of MDD at higher rates before exams than afterwards. Female students experienced symptoms of MDD (as defined by the DSM-5) including sadness, sleep disturbances, and feelings of guilt or worthlessness at a greater rate compared to males before exams. After exams, females were more likely to experience sleep disturbances and decreased energy. Second-year male students were the least likely to experience symptoms of MDD. Conclusion: First- and second-year medical students can experience symptoms of MDD surrounding exams. This study highlights the emotional burden that students may carry near exams. It underscores the importance of further research on this topic to evaluate the effect exams have on the mental health of medical students during their training.

Detection of Suicide Clusters using Small-Area Geographic Data from the Virginia Violent Death Reporting System, 2010 - 2015.

Introduction: From 1999 to 2020, the suicide rate in Virginia increased from 13.1 to 15.9 per 100,000 persons aged 10 years and older. Few studies have examined spatial patterns of suicide geographies smaller than the county level. Methods: We analyzed data from suicide decedents aged ≥10 years from 2010 through 2015 in the Virginia Violent Death Reporting System. We identified spatial clusters of high suicide rates using spatially adaptive filtering with standardized mortality ratio (SMR) significantly higher than the state SMR (p < 0.001). We compared demographic characteristics, method of injury, and suicide circumstances of decedents within each cluster to decedents outside any cluster. Results: We identified 13 high-risk suicide clusters (SMR between 1.7 and 2.0). Suicide decedents in the clusters were more likely to be older (40+ years), non-Hispanic white, widowed/divorced/separated, and less likely to have certain precipitating suicide circumstances than decedents outside the clusters. Suicide by firearm was more common in four clusters, and suicide by poisoning was more common in two clusters compared to the rest of the state. Conclusions: There are important differences between geographic clusters of suicide in Virginia. These results suggest that place-specific risk factors for suicide may be relevant for targeted suicide prevention.