Publications by authors named "Ryan M Smith"

65 Publications

Hypoglossal and Masseteric Nerve Transfer for Facial Reanimation: A Systematic Review and Meta-Analysis.

Facial Plast Surg Aesthet Med 2021 Feb 25. Epub 2021 Feb 25.

Section of Facial Plastic and Reconstructive Surgery, Department of Otorhinolaryngology-Head and Neck Surgery, Rush University Medical Center, Chicago, Illinois, USA.

Hypoglossal and masseteric nerve transfer are currently the most popular cranial nerve transfer techniques for patients with facial paralysis. The authors performed a systematic review and meta-analysis to compare functional outcomes and adverse effects of these procedures. A review of online databases was performed to include studies with four or more patients undergoing hypoglossal or masseter nerve transfer without muscle transfer or other cranial nerve transposition. Facial nerve outcomes, time to reinnervation, and adverse events were pooled and studied. A total of 71 studies were included: 15 studies included 220 masseteric-facial transfers, and 60 studies included 1312 hypoglossal-facial transfers. Oral commissure symmetry at rest was better for hypoglossal transfer (2.22 ± 1.6 mm vs. 3.62 ± 2.7 mm,  = 0.047). The composite Sunnybrook Facial Nerve Grading Scale was better for masseteric transfer (47.7 ± 7.4 vs. 33.0 ± 6.4,  < 0.001). Time to first movement (in months) was significantly faster in masseteric transfer (4.6 ± 2.6 vs. 6.3 ± 1.3,  < 0.001). Adverse effects were rare (<5%) for both procedures. Both nerve transfer techniques are effective for facial reanimation, and the surgeon should consider the nuanced differences in selecting the correct procedure for each patient.
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http://dx.doi.org/10.1089/fpsam.2020.0523DOI Listing
February 2021

Interest in Facial Cosmetic Surgery in the Time of COVID-19: A Google Trends Analysis.

Facial Plast Surg Aesthet Med 2021 Feb 24. Epub 2021 Feb 24.

Section of Facial Plastic and Reconstructive Surgery, Department of Otorhinolaryngology, Head and Neck Surgery, Rush University Medical Center, Chicago, Illinois, USA.

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http://dx.doi.org/10.1089/fpsam.2020.0605DOI Listing
February 2021

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

Am J Otolaryngol 2020 Nov - Dec;41(6):102643. Epub 2020 Jul 15.

Section of Facial Plastic and Reconstructive Surgery, Department of Otorhinolaryngology - Head and Neck Surgery, Rush University Medical Center, Chicago, IL, United States of America.

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.
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http://dx.doi.org/10.1016/j.amjoto.2020.102643DOI Listing
December 2020

Sexual Dimorphism of the Nasal Skin and Soft Tissue Envelope.

Aesthetic Plast Surg 2020 10 18;44(5):1924-1925. Epub 2020 May 18.

Section of Facial Plastic and Reconstructive Surgery, Department of Otorhinolaryngology- Head and Neck Surgery, Rush University Medical Center, 1611 W. Harrison Street; Suite 550, Chicago, IL, 60612, USA.

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 .
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http://dx.doi.org/10.1007/s00266-020-01754-7DOI Listing
October 2020

Adverse Events Associated with Absorbable Implants for the Nasal Valve: A Review of the Manufacturer and User Facility Device Experience Database.

Facial Plast Surg Aesthet Med 2020 May 18. Epub 2020 May 18.

Department of Otorhinolaryngology-Head and Neck Surgery, Rush University Medical Center, Chicago, Illinois, USA.

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http://dx.doi.org/10.1089/fpsam.2020.0126DOI Listing
May 2020

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

Aesthetic Plast Surg 2020 10 23;44(5):1531-1536. Epub 2020 Apr 23.

Section of Facial Plastic and Reconstructive Surgery, Department of Otorhinolaryngology-Head and Neck Surgery, Rush University Medical Center, 1611 W. Harrison St., Suite 550, Chicago, IL, 60612, USA.

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.
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http://dx.doi.org/10.1007/s00266-020-01720-3DOI Listing
October 2020

Nasal Skin and Soft Tissue Thickness Variation Among Differing Races and Ethnicities: An Objective Radiographic Analysis.

Facial Plast Surg Aesthet Med 2020 May/Jun;22(3):188-194. Epub 2020 Mar 26.

Section of Facial Plastic and Reconstructive Surgery, Department of Otorhinolaryngology-Head and Neck Surgery, Rush University Medical Center, Chicago, Illinois, USA.

Nasal skin and soft tissue envelope (SSTE) thickness has considerable effects on procedural planning and postoperative outcomes in rhinoplasty surgery. Objective understanding of relative SSTE thickness in patients is essential to optimal outcomes in rhinoplasty, and knowledge of its variation by demographic group is of aid to surgeons. To measure and compare nasal SSTE thickness across different races and nasal subsites and to determine whether objective variability exists for these parameters. Retrospective cross-sectional radiographic analysis was carried out on 200 adult patients, without nasal deformity, presenting to an academic otolaryngology clinic at a tertiary care academic referral center. Blinded evaluators measured nasal SSTE thickness at six sites on maxillofacial computed tomography (CT) scans and comparisons were made based on patient-reported race/ethnicity categories available in the electronic medical record. N/A Nasal SSTE thickness was measured at six predefined anatomic sites using high-resolution CT imaging. Statistical comparisons between races/ethnicities were made based on these measurements. Mean age of patients was 48.8 years, and 47% were male. Nasal SSTE showed thicker soft tissue at the sellion in Latin American (LA; mean (SD) 6.1 (1.8) mm) and white (5.8 (1.8) mm) patients vs. African American (AfA) and Asian American (AsA) patients. The supratip was thicker in AfA patients (5.2 (1.3) mm) vs. all other races. The tip SSTE was thinner in white patients (2.4 (0.7) mm) vs. all other races. Composite nasal SSTE thickness was thinner in AsA patients (3.22 (0.8) mm) relative to AfA and LA patients. SSTE thickness influences surgical planning and postoperative outcomes in rhinoplasty patients. This study supports varied thickness of the nasal SSTE among patients of different races. These data are foundational in providing a framework for developing treatment strategies specific to the SSTE properties of a multicultural patient population.
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http://dx.doi.org/10.1089/fpsam.2019.0008DOI Listing
November 2020

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

Aesthetic Plast Surg 2020 06 9;44(3):743-749. Epub 2020 Mar 9.

Section of Facial Plastic and Reconstructive Surgery, Department of Otorhinolaryngology-Head and Neck Surgery, Rush University Medical Center, 1611 W. Harrison Street; Suite 550, Chicago, IL, 60612, USA.

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.
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http://dx.doi.org/10.1007/s00266-020-01664-8DOI Listing
June 2020

An Update on Level of Evidence Trends in Facial Plastic Surgery Research.

Facial Plast Surg Aesthet Med 2020 Mar/Apr;22(2):105-109

Section of Facial Plastic and Reconstructive Surgery, Department of Otorhinolaryngology-Head and Neck Surgery, Rush University Medical Center, Chicago, Illinois.

Knowledge of the quality of evidence in facial plastic surgery research is essential for the implementation of evidence-based practices. The purpose of this study is to provide an update over the past decade as to whether the level of evidence in leading journals featuring topics in facial plastic surgery has changed in comparison with prior reports. This study is a systematic review, designed to evaluate the level of evidence observed in the facial plastic surgery literature over time. Five journals were queried using facial plastic surgery keywords for four selected years for a 10-year period. After screening, articles were assessed for the presence of various methodological traits and were evaluated for overall level of evidence. These variables were compared across the years studied to evaluate trends in level of evidence. A total of 826 articles were included for final review. For all selected years, level IV or level V evidence was the most prevalent level of evidence. Over time, significantly less level IV ( = 0.009) and significantly more level II ( = 0.007) evidence was published. The proportion of studies reporting confidence intervals ( < 0.001) and -values ( = 0.02) were significantly greater in later years. The level of evidence of facial plastic surgery literature has increased over time, as demonstrated by an increased proportion of level II evidence, decreased proportion of level IV evidence, and increased use of -values and confidence intervals. The absolute number of randomized controlled trials continues to remain low.
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http://dx.doi.org/10.1089/fpsam.2019.0003DOI Listing
August 2020

The Selfie View: Perioperative Photography in the Digital Age.

Aesthetic Plast Surg 2020 06 9;44(3):1066-1070. Epub 2020 Jan 9.

Section of Facial Plastic and Reconstructive Surgery, Department of Otorhinolaryngology-Head and Neck Surgery, Rush University Medical Center, 1611 W. Harrison Street; Suite 550, Chicago, IL, USA.

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.
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http://dx.doi.org/10.1007/s00266-019-01593-1DOI Listing
June 2020

Resources That Improve Medical Board Licensing Examination Performance.

Cureus 2019 Oct 16;11(10):e5927. Epub 2019 Oct 16.

Psychiatry, College of Osteopathic Medicine, University of New England, Biddeford, USA.

Purpose Examine the factors improving performance on national medical licensing board examinations. Rationale Accreditation Council for Graduate Medical Education (ACGME) accredited residency programs report the United States Medical Licensing Examination (USMLE) Step 1 and Comprehensive Osteopathic Licensing Examination-USA (COMLEX-USA) Level 1 scores as the most important criteria in selecting candidates to interview. Hypotheses (1) Certain resources are superior for exam preparation. (2) Certain practice tests better assess exam preparedness. (3) USMLE performance will correlate with the COMLEX-USA. Methods One-hundred and two (102) medical students were surveyed regarding preparation for and performance on COMLEX-USA Level 1 and USMLE Step 1. Results USMLE-specific question banks were positively correlated with performance on COMLEX-USA Level 1 and USMLE Step 1 while COMLEX-specific question banks showed no correlation. National Board of Medical Examiners (NBME) Comprehensive Basic Science Self Assessment (CBSSA) and National Board of Osteopathic Medical Examiners (NBOME) Comprehensive Osteopathic Medical Self-Assessment Examination (COMSAE) practice examinations were positively correlated with performance on the USMLE Step 1 and the COMLEX-USA Level 1. Scores on USMLE Step 1 and COMLEX-USA Level 1 were highly correlated. Students who took USMLE Step 1 performed better on COMLEX-USA Level 1 than those who did not. Conclusion COMLEX-specific resources may not adequately prepare students for COMLEX-USA Level 1. Students studying for COMLEX-USA Level 1 may benefit by preparing for USMLE Step 1.
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http://dx.doi.org/10.7759/cureus.5927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857833PMC
October 2019

Association of Perioperative Opioid-Sparing Multimodal Analgesia With Narcotic Use and Pain Control After Head and Neck Free Flap Reconstruction.

JAMA Facial Plast Surg 2019 Sep;21(5):446-451

Section of Facial Plastic and Reconstructive Surgery, Department of Otorhinolaryngology-Head and Neck Surgery, Rush University Medical Center, Chicago, Illinois.

Importance: An increase in narcotic prescription patterns has contributed to the current opioid epidemic in the United States. Opioid-sparing perioperative analgesia represents a means of mitigating the risk of opioid dependence while providing superior perioperative analgesia.

Objective: To assess whether multimodal analgesia (MMA) is associated with reduced narcotic use and improved pain control compared with traditional narcotic-based analgesics at discharge and in the immediate postoperative period after free flap reconstructive surgery.

Design, Setting, And Participants: This retrospective cohort study assessed a consecutive sample of 65 patients (28 MMA, 37 controls) undergoing free flap reconstruction of a through-and-through mucosal defect within the head and neck region at a tertiary academic referral center from June 1, 2017, to November 30, 2018. Patients and physicians were not blinded to the patients' analgesic regimen. Patients' clinical courses were followed up for 30 days postoperatively.

Interventions: Patients were administered a preoperative, intraoperative, and postoperative analgesia regimen consisting of scheduled and as-needed neuromodulating and anti-inflammatory medications, with narcotic medications reserved for refractory cases. Control patients were administered traditional narcotic-based analgesics as needed.

Main Outcomes And Measures: Narcotic doses administered during the perioperative period and at discharge were converted to morphine-equivalent doses (MEDs) for comparison. Postoperative Defense and Veterans Pain Rating Scale pain scores (ranging from 0 [no pain] to 10 [worst pain imaginable]) were collected for the first 72 hours postoperatively as a patient-reported means of analyzing effectiveness of analgesia.

Results: A total of 28 patients (mean [SD] age, 64.1 [12.3] years; 17 [61%] male) were included in the MMA group and 37 (mean [SD] age, 65.0 [11.0] years; 22 [59%] male) in the control group. The number of MEDs administered postoperatively was 10.0 (interquartile range [IQR], 2.7-23.1) in the MMA cohort and 89.6 (IQR, 60.0-104.5) in the control cohort (P < .001). Mean (SD) Defense and Veterans Pain Rating Scale pain scores postoperatively were 2.05 (1.41) in the MMA cohort and 3.66 (1.99) in the control cohort (P = .001). Median number of MEDs prescribed at discharge were 0 (IQR, 0-18.8) in the MMA cohort and 300.0 (IQR, 262.5-412.5) in the control cohort (P < .001).

Conclusions And Relevance: The findings suggest that after free flap reconstruction, MMA is associated with reduced narcotic use at discharge and in the immediate postoperative period and with superior analgesia as measured by patient-reported pain scores. Patients receiving MMA achieved improved pain control, and the number of narcotic prescriptions in circulation were reduced.

Level Of Evidence: 3.
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http://dx.doi.org/10.1001/jamafacial.2019.0612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692678PMC
September 2019

Spontaneous Otogenic Pneumocephalus: Case Series and Update on Management.

J Neurol Surg B Skull Base 2019 Aug 19;80(4):424-430. Epub 2018 Nov 19.

Department of Otorhinolaryngology, Rush University Medical Center, Chicago, Illinois, United States.

 This study is aimed to report the largest independent case series of spontaneous otogenic pneumocephalus (SOP) and review its pathophysiology, clinical presentation, and treatment.  Four patients underwent a middle cranial fossa approach for repair of the tegmen tympani and tegmen mastoideum. A comprehensive review of the literature regarding this disease entity was performed.  U.S. tertiary academic medical center.  Patients presenting to the lead author's clinic or to the emergency department with radiographic evidence of SOP. Symptoms included headache, otalgia, and neurologic deficits.  Patients were assessed for length of stay, postoperative length of stay, and neurologic outcome. Three of four patients returned to their neurologic baseline following repair.  Four patients were successfully managed via a middle cranial fossa approach to repairing the tegmen mastoideum.  The middle cranial fossa approach is an effective strategy to repair defects of the tegmen mastoideum. SOP remains a clinically rare disease, with little published information on its diagnosis and treatment.
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http://dx.doi.org/10.1055/s-0038-1676036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635110PMC
August 2019

Enhanced recovery after surgery in head and neck surgery: Reduced opioid use and length of stay.

Laryngoscope 2020 05 17;130(5):1227-1232. Epub 2019 Jul 17.

Department of Otorhinolaryngology-Head and Neck Surgery, Rush University Medical Center, Chicago, Illinois, U.S.A.

Objectives: Enhanced recovery after surgery (ERAS) protocols were first developed in colorectal surgery and sought to standardize patient care. There have been several studies in the head and neck surgical literature looking at outcomes after ERAS protocol, but no studies focusing on narcotic use and length of stay. This study aimed to evaluate narcotic usage and length of stay, in addition to several other outcomes, following the implementation of an ERAS protocol.

Methods: A head and neck-specific ERAS protocol was implemented at this tertiary care center beginning July 2017. A retrospective cohort study was performed comparing this cohort to that of a retrospective control group. Outcomes included mean morphine equivalent dose, mean pain score, and percentage of patients prescribed narcotics on discharge. Secondary outcomes included ICU and total length of stay.

Results: The mean morphine equivalent dose (MED) administered within 72 hours postoperatively was significantly lower in the ERAS group (17.5 ± 46.0 mg vs. 82.7 ± 116.1 mg, P < .001). Average postoperative pain scores in the first 72 hours were lower in the ERAS group (2.6 ± 1.8 vs. 3.6 ± 1.9; P < .001). The average length of stay was shorter for ERAS patients (7.8 ± 4.8 vs. 9.7 ± 4.7 days, P = .008); however, there was no significant difference in ICU length of stay.

Conclusion: Following implementation of an ERAS protocol, patients undergoing head and neck surgery had decreased narcotic use in the immediate postoperative period and at discharge, while also demonstrating improved postoperative analgesia.

Level Of Evidence: Level 3 Laryngoscope, 130:1227-1232, 2020.
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http://dx.doi.org/10.1002/lary.28191DOI Listing
May 2020

Reconstruction of the Ear.

Facial Plast Surg Clin North Am 2019 Feb;27(1):95-104

Division of Facial Plastic and Reconstructive Surgery, Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, 601 North Caroline Street, 6th Floor, Baltimore, MD 21287, USA.

Skin cancer is a common indication for reconstructive surgery of the ear. The unique anatomy of the external ear makes the restoration of form and function challenging for the reconstructive surgeon. This article reviews the relevant anatomy of the ear, defines the goals of reconstruction, outlines the assessment of defects based on location, and describes specific surgical techniques useful in auricular reconstruction.
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http://dx.doi.org/10.1016/j.fsc.2018.08.010DOI Listing
February 2019

Difficult Necks and Unresolved Problems in Neck Rejuvenation.

Clin Plast Surg 2018 Oct 10;45(4):611-622. Epub 2018 Aug 10.

Division of Facial Plastic and Reconstructive Surgery, Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, 601 North Caroline Street, 6th Floor, Baltimore, MD 21287, USA; Facial Plastic Surgicenter, 1838 Greene Tree Road, Suite 370, Baltimore, MD 21208, USA. Electronic address:

Neck rejuvenation attempts to correct the unattractive features that result from the process of facial aging. The aesthetic goals of surgery include creating a well-defined jaw contour, optimal cervicomental angle, smooth-appearing skin, and a healthy redistribution of soft tissue volume. Unique patient characteristics create inherent challenges that may limit the degree to which improvement can be made. Psychological expectations and motivations influence patient satisfaction and must be understood through careful evaluation and counseling. This article describes common difficult situations encountered during neck rejuvenation and discusses unresolved problems. Several clinical examples along with specific surgical solutions are included.
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http://dx.doi.org/10.1016/j.cps.2018.06.009DOI Listing
October 2018

Considerations for Temporomandibular Joint Procurement in Vascularized Composite Allotransplantation.

J Craniofac Surg 2018 Oct;29(7):1742-1746

Department of Plastic and Reconstructive Surgery, Johns Hopkins Hospital, Baltimore, MD.

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.
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http://dx.doi.org/10.1097/SCS.0000000000004710DOI Listing
October 2018

Use of Objective Metrics in Dynamic Facial Reanimation: A Systematic Review.

JAMA Facial Plast Surg 2018 Dec;20(6):501-508

Division of Facial Plastic and Reconstructive Surgery, Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland.

Importance: Facial nerve deficits cause significant functional and social consequences for those affected. Existing techniques for dynamic restoration of facial nerve function are imperfect and result in a wide variety of outcomes. Currently, there is no standard objective instrument for facial movement as it relates to restorative techniques.

Objective: To determine what objective instruments of midface movement are used in outcome measurements for patients treated with dynamic methods for facial paralysis.

Data Sources: Database searches from January 1970 to June 2017 were performed in PubMed, Embase, Cochrane Library, Web of Science, and Scopus. Only English-language articles on studies performed in humans were considered. The search terms used were ("Surgical Flaps"[Mesh] OR "Nerve Transfer"[Mesh] OR "nerve graft" OR "nerve grafts") AND (face [mh] OR facial paralysis [mh]) AND (innervation [sh]) OR ("Face"[Mesh] OR facial paralysis [mh]) AND (reanimation [tiab]).

Study Selection: Two independent reviewers evaluated the titles and abstracts of all articles and included those that reported objective outcomes of a surgical technique in at least 2 patients.

Main Outcomes And Measures: The presence or absence of an objective instrument for evaluating outcomes of midface reanimation. Additional outcome measures were reproducibility of the test, reporting of symmetry, measurement of multiple variables, and test validity.

Results: Of 241 articles describing dynamic facial reanimation techniques, 49 (20.3%) reported objective outcome measures for 1898 patients. Of those articles reporting objective measures, there were 29 different instruments, only 3 of which reported all outcome measures.

Conclusions And Relevance: Although instruments are available to objectively measure facial movement after reanimation techniques, most studies do not report objective outcomes. Of objective facial reanimation instruments, few are reproducible and able to measure symmetry and multiple data points. To accurately compare objective outcomes in facial reanimation, a reproducible, objective, and universally applied instrument is needed.
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http://dx.doi.org/10.1001/jamafacial.2018.0398DOI Listing
December 2018

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

Cogn Behav Neurol 2018 06;31(2):79-85

Department of Pharmacology.

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.
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http://dx.doi.org/10.1097/WNN.0000000000000153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021134PMC
June 2018

Advancing psychiatric pharmacogenomics using drug development paradigms.

Authors:
Ryan M Smith

Pharmacogenomics 2017 Oct 4;18(15):1459-1467. Epub 2017 Oct 4.

Division of Pharmaceutics & Translational Therapeutics, Department of Pharmaceutical Sciences & Experimental Therapeutics, The University of Iowa, College of Pharmacy, 115 South Grand Avenue, S427 Pharmacy Building, Iowa City, IA 52242, USA.

Drugs used to treat psychiatric disorders, even when taken as directed, fail to provide adequate relief for a sizeable proportion of patients. Despite our advancements in understanding human genetics and development of high-throughput tools to probe variation, pharmacogenomics has yielded marginal ability to predict drug response for psychiatric disorders. Here, I review the current pharmacogenomics paradigm, identifying opportunities to incorporate drug development strategies designed to increase the probability of delivering a successful molecule to the clinic. This includes using in-depth pharmacokinetic profiles, clear measures of target engagement and target-specific pharmacodynamic responses orthogonal to clinical response. The complex pharmacological profiles psychiatric drugs require re-examination of simplified clinical response-oriented pharmacogenetic hypotheses, in favor of a more complete patient profile.
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http://dx.doi.org/10.2217/pgs-2017-0104DOI Listing
October 2017

Brain Changes in Responders vs. Non-Responders in Chronic Migraine: Markers of Disease Reversal.

Front Hum Neurosci 2016 6;10:497. Epub 2016 Oct 6.

Center for Pain and the Brain, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's HospitalBoston, MA, USA; Department of Anaesthesia, Harvard Medical SchoolBoston, MA, USA.

The aim of this study was to identify structural and functional brain changes that accompanied the transition from chronic (CM; ≥15 headache days/month) to episodic (EM; <15 headache days/month) migraine following prophylactic treatment with onabotulinumtoxinA (BoNT-A). Specifically, we examined whether CM patients responsive to prophylaxis (responders; = 11), as evidenced by a reversal in disease status (defined by at least a 50% reduction in migraine frequency and <15 headache days/month), compared to CM patients whose migraine frequency remained unchanged (non-responders; = 12), showed differences in cortical thickness using surface-based morphometry. We also investigated whether areas showing group differences in cortical thickness displayed altered resting-state functional connectivity (RS-FC) using seed-to-voxel analyses. Migraine characteristics measured across groups included disease duration, pain intensity and headache frequency. Patient reports of headache frequency over the 4 weeks prior to (pre-treatment) and following (post-treatment) prophylaxis were compared (post minus pre) and this measure served as the clinical endpoint that determined group assignment. All patients were scanned within 2 weeks of the post-treatment visit. Results revealed that responders showed significant cortical thickening in the right primary somatosensory cortex (SI) and anterior insula (aINS), and left superior temporal gyrus (STG) and pars opercularis (ParsOp) compared to non-responders. In addition, disease duration was negatively correlated with cortical thickness in fronto-parietal and temporo-occipital regions in responders but not non-responders, with the exception of the primary motor cortex (MI) that showed the opposite pattern; disease duration was positively associated with MI cortical thickness in responders versus non-responders. Our seed-based RS-FC analyses revealed anti-correlations between the SI seed and lateral occipital (LOC) and dorsomedial prefrontal cortices (DMPFC) in responders, whereas non-responders showed increased connectivity between the ParsOp seed and LOC. Overall, our findings revealed distinct morphometric and functional brain changes in CM patients that reverted to EM following prophylactic treatment compared to CM patients that showed no change in disease status. Elucidating the CNS changes involved in disease reversal may be critical to discovering interventions that prevent or slow the progression of CM. Such changes may aid in the evaluation of treatments as well as provide markers for disease "de-chronification".
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http://dx.doi.org/10.3389/fnhum.2016.00497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052273PMC
October 2016

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

BMC Genet 2016 Jan 6;17:16. Epub 2016 Jan 6.

Tailored Therapeutics, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN, ᅟ.

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.
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http://dx.doi.org/10.1186/s12863-015-0325-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702415PMC
January 2016

Chronic CSF leak causing syringomyelia and pseudo-Arnold-Chiari malformation.

Neurology 2015 Dec;85(22):1994

From the Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1212/WNL.0000000000002178DOI Listing
December 2015

Selectivity of Terahertz Gas-Phase Spectroscopy.

Anal Chem 2015 Nov 15;87(21):10679-83. Epub 2015 Oct 15.

Department of Chemistry and Optical Science and Technology Center, University of Iowa , Iowa City, Iowa 52242, United States.

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.
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http://dx.doi.org/10.1021/acs.analchem.5b03028DOI Listing
November 2015

Allele-Selective Transcriptome Recruitment to Polysomes Primed for Translation: Protein-Coding and Noncoding RNAs, and RNA Isoforms.

PLoS One 2015 2;10(9):e0136798. Epub 2015 Sep 2.

Center for Pharmacogenomics, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America; Department of Medical Genetics, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.

mRNA translation into proteins is highly regulated, but the role of mRNA isoforms, noncoding RNAs (ncRNAs), and genetic variants remains poorly understood. mRNA levels on polysomes have been shown to correlate well with expressed protein levels, pointing to polysomal loading as a critical factor. To study regulation and genetic factors of protein translation we measured levels and allelic ratios of mRNAs and ncRNAs (including microRNAs) in lymphoblast cell lines (LCL) and in polysomal fractions. We first used targeted assays to measure polysomal loading of mRNA alleles, confirming reported genetic effects on translation of OPRM1 and NAT1, and detecting no effect of rs1045642 (3435C>T) in ABCB1 (MDR1) on polysomal loading while supporting previous results showing increased mRNA turnover of the 3435T allele. Use of high-throughput sequencing of complete transcript profiles (RNA-Seq) in three LCLs revealed significant differences in polysomal loading of individual RNA classes and isoforms. Correlated polysomal distribution between protein-coding and non-coding RNAs suggests interactions between them. Allele-selective polysome recruitment revealed strong genetic influence for multiple RNAs, attributable either to differential expression of RNA isoforms or to differential loading onto polysomes, the latter defining a direct genetic effect on translation. Genes identified by different allelic RNA ratios between cytosol and polysomes were enriched with published expression quantitative trait loci (eQTLs) affecting RNA functions, and associations with clinical phenotypes. Polysomal RNA-Seq combined with allelic ratio analysis provides a powerful approach to study polysomal RNA recruitment and regulatory variants affecting protein translation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0136798PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558023PMC
May 2016

Analyzing allele specific RNA expression using mixture models.

BMC Genomics 2015 Aug 1;16:566. Epub 2015 Aug 1.

Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, OH, 43210, USA.

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.
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http://dx.doi.org/10.1186/s12864-015-1749-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521363PMC
August 2015

Numb Chin Syndrome.

Curr Pain Headache Rep 2015 Sep;19(9):44

Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55901, USA.

"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.
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http://dx.doi.org/10.1007/s11916-015-0515-yDOI Listing
September 2015

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

BMC Genomics 2015 18;16 Suppl 8:S8. Epub 2015 Jun 18.

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.
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http://dx.doi.org/10.1186/1471-2164-16-S8-S8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480832PMC
March 2016

Orthostatic headache from supratentorial meningioma.

Cephalalgia 2015 Nov 9;35(13):1214. Epub 2015 Feb 9.

Department of Neurology, Mayo Clinic, USA

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http://dx.doi.org/10.1177/0333102415570763DOI Listing
November 2015

Genetic influences on nicotinic α5 receptor (CHRNA5) CpG methylation and mRNA expression in brain and adipose tissue.

Genes Environ 2015 1;37:14. Epub 2015 Oct 1.

Center for Pharmacogenomics, The Ohio State University, Columbus, OH 43210 USA ; Department of Pharmacology, The Ohio State University, 5184A Graves Hall, 333. W. 10th Ave., Columbus, OH 43210 USA.

Introduction: The nicotinic α5 receptor subunit, encoded by CHRNA5, harbors multiple functional single nucleotide polymorphisms (SNPs) that affect mRNA expression and alter the encoded protein. These polymorphisms are most notably associated with drug-taking behaviors and cognition. We previously identified common SNPs in a distant regulatory element (DRE) that increase CHRNA5 mRNA expression in the human prefrontal cortex (PFC) and confer risk for nicotine dependence. Genome-wide epigenetic studies in PFC and adipose tissue find strong effects of the DRE SNPs on CpG methylation. However, it is unclear whether DRE SNPs influence CpG methylation en route to modulating CHRNA5 mRNA expression. It is also unclear whether these polymorphisms affect expression in other brain regions, especially those mediating drug-taking behaviors.

Results: By measuring total and allelic CHRNA5 mRNA expression in human habenula and putamen autopsy tissues, we found that CHRNA5 DRE variants considerably increase mRNA expression by up to 3.5-fold in both brain regions. Our epigenetic analysis finds no association between CpG methylation and CHRNA5 mRNA expression in the PFC or adipose tissues.

Conclusions: These finding suggests the mechanisms responsible for the genetic modulation of CpG methylation and mRNA expression are independent despite the DRE SNPs being highly associated with both measures. Our findings support a strong association between the DRE SNPs and mRNA expression or CpG methylation in the brain and periphery, but the independence of the two measures leads us to conclude that environmental factors affecting CpG methylation do not appear to directly modulate gene expression.
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http://dx.doi.org/10.1186/s41021-015-0020-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917931PMC
June 2016