BMJ Open. 2018 Oct 15;8(10):e022752. doi: 10.1136/bmjopen-2018-022752.
Obstructive sleep apnoea and the risk for coronary heart disease and type 2 diabetes: a longitudinal population-based study in Finland.
Strausz S1,2,3, Havulinna AS3,4, Tuomi T3,5,6, Bachour A7, Groop L3,8, Mäkitie A9, Koskinen S4, Salomaa V4, Palotie A3,10,11,12,13, Ripatti S#3,14, Palotie T#1,2.
Author information
1
Department of Oral and Maxillofacial Diseases, Helsinki University Hospital, Helsinki, Finland.
2
Orthodontics, Department of Oral and Maxillofacial Diseases, Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
3
Institute for Molecular Medicine Finland (FIMM/HiLIFE), University of Helsinki, Helsinki, Finland.
4
National Institute for Health and Welfare, Helsinki, Finland.
5
Endocrinology, Abdominal Centre, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
6
Diabetes and Obesity Research Program, University of Helsinki and Folkhälsan Research Center, Helsinki, Finland.
7
Sleep Unit, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.
8
Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden.
9
Department of Otorhinolaryngology-Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
10
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
11
Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
12
Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA.
13
The Medical and Population Genomics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
14
Department of Public Health, University of Helsinki, Helsinki, Finland.
#
Contributed equally
Abstract
OBJECTIVE:
To evaluate if obstructive sleep apnoea (OSA) modifies the risk of coronary heart disease, type 2 diabetes (T2D) and diabetic complications in a gender-specific fashion.

DESIGN AND SETTING:
A longitudinal population-based study with up to 25-year follow-up data on 36 963 individuals (>500 000 person years) from three population-based cohorts: the FINRISK study, the Health 2000 Cohort Study and the Botnia Study.

MAIN OUTCOME MEASURES:
Incident coronary heart disease, diabetic kidney disease, T2D and all-cause mortality from the Finnish National Hospital Discharge Register and the Finnish National Causes-of-Death Register.

RESULTS:
After adjustments for age, sex, region, high-density lipoprotein (HDL) and total cholesterol, current cigarette smoking, body mass index, hypertension, T2D baseline and family history of stroke or myocardial infarction, OSA increased the risk for coronary heart disease (HR=1.36, p=0.0014, 95% CI 1.12 to 1.64), particularly in women (HR=2.01, 95% CI 1.31 to 3.07, p=0.0012). T2D clustered with OSA independently of obesity (HR=1.48, 95% CI 1.26 to 1.73, p=9.11×[Formula: see text]). The risk of diabetic kidney disease increased 1.75-fold in patients with OSA (95% CI 1.13 to 2.71, p=0.013). OSA increased the risk for coronary heart disease similarly among patients with T2D and in general population (HR=1.36). All-cause mortality was increased by OSA in diabetic individuals (HR=1.35, 95% CI 1.06 to 1.71, p=0.016).

CONCLUSION:
OSA is an independent risk factor for coronary heart disease, T2D and diabetic kidney disease. This effect is more pronounced even in women, who until now have received less attention in diagnosis and treatment of OSA than men.

© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

KEYWORDS:
coronary heart disease; diabetic kidney disease; longitudinal; mortality; obstructive sleep apnea; type 2 diabetes

PMID: 30327404 PMCID: PMC6194468 DOI: 10.1136/bmjopen-2018-022752
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Select item 30325698
142.
Otolaryngol Head Neck Surg. 2019 Feb;160(2):246-254. doi: 10.1177/0194599818807918. Epub 2018 Oct 16.
Cleft Palates and Occlusal Outcomes in Pierre Robin Sequence.
Do JBA1, Bellerive A2, Julien AS3, Leclerc JE4.
Author information
1
1 Department of Otolaryngology-Head and Neck Surgery, Université Laval, Quebec City, Quebec, Canada.
2
2 Faculty of Dentistry, Université Laval, Quebec City, Quebec, Canada.
3
3 Clinical Research Platform, CHU de Québec-Université Laval Research Centre, Quebec City, Quebec, Canada.
4
4 Department of Otolaryngology-Head and Neck Surgery, Centre Hospitalier Universitaire de Québec, Quebec City, Quebec, Canada.
Abstract
OBJECTIVE:
To assess the dental class occlusion and lateral cephalometry of children with conservatively treated Pierre Robin sequence (PRS) and to identify associations between these findings and prepalatoplasty cleft palate measurements.

STUDY DESIGN:
Retrospective cohort study.

SUBJECTS AND METHODS:
Among 22 patients with PRS, the following data were prospectively collected: demographics and preoperative cleft palate measurements. After patients reached age 6 years, an orthodontist assessed dental occlusion class and performed a lateral cephalometric analysis. PRS cephalometric data were compared with reference population values. Bivariate logistic regression was used to test the association with malocclusion class. Results are presented as odds ratios with 95% profile likelihood confidence intervals. The association between cleft measurements and cephalometric parameters was tested with Spearman's correlation ( rs).

RESULTS:
All 22 patients had bimaxillary hypoplasia and were prone to hyperdivergency, with a 41% rate of dental class III malocclusion. An increased anterior growth of the still retrusive mandible mostly accounts for the occurrence of the class III malocclusion in PRS (class II SNB = 74.3° vs class III SNB = 77.6°, P = .04). A larger cleft at the time of the cleft repair (mean, 11 months) was associated with increased mandibular retrusion (smaller SNB angle, rs = -0.5, P = .02).

CONCLUSIONS:
The 41% rate of class III malocclusion among these conservatively treated patients needs to be considered in the choice of the initial airway approach. The future impact of early mandibular advancement will have to be determined.

KEYWORDS:
Pierre Robin sequence; cleft palate; malocclusion; mandibular advancement; mandibular retrusion; maxillary advancement; maxillary retrusion; orthognathic surgery

PMID: 30325698 DOI: 10.1177/0194599818807918
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143.
Otolaryngol Head Neck Surg. 2019 Jan;160(1):49-56. doi: 10.1177/0194599818802183. Epub 2018 Oct 16.
Utility of Intraoperative Frozen Section in Large Thyroid Nodules.
Bollig CA1, Jorgensen JB1, Zitsch RP 3rd1, Dooley LM1.
Author information
1
1 Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Missouri, Columbia, Missouri, USA.
Abstract
OBJECTIVE:
To determine if the routine use of intraoperative frozen section (iFS) results in cost savings among patients with nodules >4 cm with nonmalignant cytology undergoing a thyroid lobectomy.

STUDY DESIGN:
Case series with chart review; cost minimization analysis.

SETTING:
Single academic center.

SUBJECTS AND METHODS:
Records were reviewed on a consecutive sample of 48 patients with thyroid nodules >4 cm and nonmalignant cytology who were undergoing thyroid lobectomy in which iFS was performed between 2010 and 2015. A decision tree model of thyroid lobectomy with iFS was created. Comparative parameters were obtained from the literature. A cost minimization analysis was performed comparing lobectomy with and without iFS and the need for completion thyroidectomy with costs estimated according to 2014 data from Medicare, the Bureau of Labor Statistics, and the Nationwide Inpatient Sample.

RESULTS:
The overall malignancy rate was 25%, and 33% of these malignancies were identified intraoperatively. When the malignancy rates obtained from our cohort were applied, performing routine iFS was the less costly scenario, resulting in a savings of $486 per case. When the rate of malignancy identified on iFS was adjusted, obtaining iFS remained the less costly scenario as long as the rate of malignancies identified on iFS exceeded 12%. If patients with follicular lesions on cytology were excluded, 50% of malignancies were identified intraoperatively, resulting in a savings of $768 per case.

CONCLUSIONS:
For patients with nodules >4 cm who are undergoing a diagnostic lobectomy, the routine use of iFS may result in decreased health care utilization. Additional cost savings could be obtained if iFS is avoided among patients with follicular lesions.

KEYWORDS:
cost analysis; frozen section; large thyroid nodule; thyroid cancer

PMID: 30322356 DOI: 10.1177/0194599818802183
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144.
Otolaryngol Head Neck Surg. 2019 Jan;160(1):107-115. doi: 10.1177/0194599818803584. Epub 2018 Oct 16.
Pathologic Fibroblasts in Idiopathic Subglottic Stenosis Amplify Local Inflammatory Signals.
Morrison RJ1,2, Katsantonis NG1, Motz KM3, Hillel AT3, Garrett CG1, Netterville JL1, Wootten CT1, Majka SM4, Blackwell TS4,5, Drake WP6, Gelbard A1.
Author information
1
1 Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University, Nashville, Tennessee, USA.
2
2 Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, USA.
3
3 Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins, Baltimore, Maryland, USA.
4
4 Department of Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee, USA.
5
5 Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, USA.
6
6 Division of Infectious Disease, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
Abstract
OBJECTIVE:
To characterize the phenotype and function of fibroblasts derived from airway scar in idiopathic subglottic stenosis (iSGS) and to explore scar fibroblast response to interleukin 17A (IL-17A).

STUDY DESIGN:
Basic science.

SETTING:
Laboratory.

SUBJECTS AND METHODS:
Primary fibroblast cell lines from iSGS subjects, idiopathic pulmonary fibrosis subjects, and normal control airways were utilized for analysis. Protein, molecular, and flow cytometric techniques were applied in vitro to assess the phenotype and functional response of disease fibroblasts to IL-17A.

RESULTS:
Mechanistically, IL-17A drives iSGS scar fibroblast proliferation ( P < .01), synergizes with transforming growth factor ß1 to promote extracellular matrix production (collagen and fibronectin; P = .04), and directly stimulates scar fibroblasts to produce chemokines (chemokine ligand 2) and cytokines (IL-6 and granulocyte-macrophage colony-stimulating factor) critical to the recruitment and differentiation of myeloid cells ( P < .01). Glucocorticoids abrogated IL-17A-dependent iSGS scar fibroblast production of granulocyte-macrophage colony-stimulating factor ( P = .02).

CONCLUSION:
IL-17A directly drives iSGS scar fibroblast proliferation, synergizes with transforming growth factor ß1 to promote extracellular matrix production, and amplifies local inflammatory signaling. Glucocorticoids appear to partially abrogate fibroblast-dependent inflammatory signaling. These results offer mechanistic support for future translational study of clinical reagents for manipulation of the IL-17A pathway in iSGS patients.

KEYWORDS:
IL-17; IL-17A; fibroblast; iSGS; idiopathic subglottis stenosis; laryngotracheal stenosis; tracheal stenosis

PMID: 30322354 PMCID: PMC6389372 DOI: 10.1177/0194599818803584
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Select item 30322341
145.
Otolaryngol Head Neck Surg. 2019 Feb;160(2):359-360. doi: 10.1177/0194599818806464. Epub 2018 Oct 16.
Lipochoristoma of the Internal Auditory Canal: Long-Term Surveillance.
Kedarisetty S1, Surapaneni K2.
Author information
1
1 Department of Otolaryngology, Head and Neck Surgery, Temple University Hospital, Philadelphia, Pennsylvania, USA.
2
2 Department of Radiology, Temple University Hospital, Philadelphia, Pennsylvania, USA.
KEYWORDS:
CPA; IAC; lipochoristoma; lipoma; vestibular schwannoma

PMID: 30322341 DOI: 10.1177/0194599818806464
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146.
Otolaryngol Head Neck Surg. 2019 Feb;160(2):223-231. doi: 10.1177/0194599818805673. Epub 2018 Oct 9.
The Effect of Sphenopalatine Block on the Postoperative Pain of Endoscopic Sinus Surgery: A Meta-analysis.
Kim DH1, Kang H2, Hwang SH2.
Author information
1
1 Department of Otolaryngology-Head and Neck Surgery, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
2
2 Department of Otolaryngology-Head and Neck Surgery, Bucheon St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Abstract
OBJECTIVES:
The use of sphenopalatine ganglion block (SPGB) with a local anesthetic to decrease postoperative pain after endoscopic sinus surgery (ESS) is controversial. We investigated the role of a perioperative SPB to minimize postoperative pain related to ESS in patients with chronic sinusitis through a systematic review of the relevant literature.

DATA SOURCES:
PubMed, SCOPUS, Google Scholar, Embase, and the Cochrane Register of Controlled Trials.

REVIEW METHODS:
We screened the relevant literature published before June 2018. Eight articles that compared perioperative SPGB (treatment group) with a placebo or no treatment (control group) were included for this analysis of the outcomes, which included perioperative morbidities in ESS. For quantitative variables, the standardized mean difference was applied to standardize and summate the results of the studies, and the odds ratio was used in outcome of incidence analysis.

RESULTS:
Intraoperative bleeding ( P < .0001), postoperative pain ( P = .0001), nausea and vomiting ( P = .0117), and recovery from sedation ( P < .0001) in the treatment group were significantly reduced compared with the control group. No significant adverse effects were reported in the enrolled studies. In subgroup analyses according to the SPGB approach (transoral or transnasal), the transnasal approach showed higher positive effects on intraoperative bleeding and postoperative pain compared to the transoral approach.

CONCLUSION:
In our study, SPGB combined with a local anesthetic for ESS effectively reduced intra-and postoperative morbidities. This procedure showed no significant adverse effects. Given the ease and effectiveness of this procedure, the transnasal approach should be highly recommended as a routine procedure compared to the transoral approach.

KEYWORDS:
adverse effect; bleeding; endoscopic sinus surgery; meta-analysis; postoperative pain; sphenopalatine ganglion block

PMID: 30296912 DOI: 10.1177/0194599818805673
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147.
Otolaryngol Head Neck Surg. 2019 Jan;160(1):63-69. doi: 10.1177/0194599818802224. Epub 2018 Oct 9.
Intraductal Pneumatic Lithotripsy after Extended Transoral Duct Surgery in Submandibular Sialolithiasis.
Koch M1, Schapher M1, Mantsopoulos K1, Goncalves M1, Iro H1.
Author information
1
1 Department of Otorhinolaryngology-Head and Neck Surgery, University of Erlangen-Nuremberg, Erlangen, Germany.
Abstract
OBJECTIVE:
Persistent, residual, or recurrent stones after transoral duct surgery are always associated with hilar to intraparenchymal and/or multiple sialolithiasis, causing difficulties in the treatment. This study was performed to assess the value of intraductal lithotripsy in the treatment of persistent, residual, or recurrent sialolithiasis after extended duct surgery in the submandibular gland.

STUDY DESIGN:
Retrospective study covering February 2015 to June 2018.

STUDY SETTING:
Tertiary referral center for salivary gland diseases.

SUBJECTS AND METHODS:
After extended ductal surgery, 39 patients presenting with persistent, residual, or recurrent stones were treated. Four patients had persistent stones; 16 had residual stones; and 19 presented with recurrent stones. Among these patients, 50 stones were treated with intraductal pneumatic lithotripsy. Fragmentation rate, stone-free rate, and symptom-free rate after treatment with intraductal lithotripsy were outcome measures.

RESULTS:
Of the 39 patients, 97.4% became stone-free, and all were symptom-free. Ninety-eight percent of the stones were completely fragmented. For 23.1% of the patients, >1 stone was treated with intraductal lithotripsy. All patients with persistent stones, 93.7% of those with residual stones, and all with recurrent stones became stone-free and symptom-free. No severe complications developed.

CONCLUSIONS:
This study shows that patients presenting with difficult and/or multiple sialolithiasis after extended transoral submandibular duct surgery can be treated with success rates >97%. For multiple sialolithiasis in particular, a multimodal treatment approach with interventional sialendoscopy and intraductal lithotripsy as a central element is a prerequisite for success, as this enables the most difficult part to be performed with high success rates.

KEYWORDS:
intraductal lithotripsy; salivary; sialendoscopy; sialolithiasis; stones; submandibular

PMID: 30296893 DOI: 10.1177/0194599818802224
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148.
Otolaryngol Head Neck Surg. 2019 Feb;160(2):343-346. doi: 10.1177/0194599818805006. Epub 2018 Oct 9.
Posterior Inferior Turbinate Hypertrophy (PITH).
McCoul ED1,2,3, Todd CA3, Riley CA3.
Author information
1
1 Department of Otorhinolaryngology, Ochsner Clinic Foundation, New Orleans, Louisiana, USA.
2
2 University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, Louisiana, USA.
3
3 Department of Otolaryngology-Head and Neck Surgery, Tulane University School of Medicine, New Orleans, Louisiana, USA.
Abstract
Hypertrophy of the soft tissue of the posterior inferior turbinate (PITH) may be observed during nasal endoscopy, although the clinical significance is not understood. We report a cross-sectional study of consecutive new patients undergoing baseline nasal endoscopy in a tertiary rhinology clinic. Subjects completed 22-Item Sinonasal Outcome Test (SNOT-22) and Nasal Obstruction Symptom Evaluation (NOSE) questionnaires. Of 391 subjects screened, PITH was present in 62 (15.9%), with a female predominance. The prevalence of allergic rhinitis and chronic rhinosinusitis was comparable between PITH and non-PITH groups. Nonpurulent exudate flowing from the posterior inferior turbinate into the nasopharynx was more prevalent in association with PITH (83.9% vs 14.3%, P < .001). Mean SNOT-22 scores and NOSE scores were not significantly different between PITH and non-PITH groups. This preliminary study suggests that PITH is a common physical finding with unclear etiology and should be the subject of further investigation.

KEYWORDS:
nasal endoscopy; turbinate

PMID: 30296890 DOI: 10.1177/0194599818805006
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149.
J Immunother Cancer. 2018 Oct 1;6(1):98. doi: 10.1186/s40425-018-0406-y.
Ibuprofen supports macrophage differentiation, T cell recruitment, and tumor suppression in a model of postpartum breast cancer.
Pennock ND1, Martinson HA2, Guo Q1, Betts CB1, Jindal S1, Tsujikawa T3, Coussens LM1,4, Borges VF5,6, Schedin P7,8,9,10.
Author information
1
Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 SW Moody Ave, Portland, OR, 97201, USA.
2
WWAMI School of Medical Education, University of Alaska Anchorage, 3211 Providence Dr, Anchorage, AK, 99508, USA.
3
Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Kyoto Prefecture, Japan.
4
Knight Cancer Institute, Oregon Health & Science University, 2720 SW Moody Ave, Portland, OR, 97201, USA.
5
Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, MS8117, RC-1S, 8401K, 12801 E 17th Ave, Aurora, CO, 80045, USA.
6
Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, 1665 Aurora Court, Aurora, CO, 80045, USA.
7
Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 SW Moody Ave, Portland, OR, 97201, USA. Schedin@ohsu.edu.
8
Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, MS8117, RC-1S, 8401K, 12801 E 17th Ave, Aurora, CO, 80045, USA. Schedin@ohsu.edu.
9
Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, 1665 Aurora Court, Aurora, CO, 80045, USA. Schedin@ohsu.edu.
10
Knight Cancer Institute, Oregon Health & Science University, 2720 SW Moody Ave, Portland, OR, 97201, USA. Schedin@ohsu.edu.
Abstract
BACKGROUND:
Women diagnosed with breast cancer within 5 years postpartum (PPBC) have poorer prognosis than age matched nulliparous women, even after controlling for clinical variables known to impact disease outcomes. Through rodent modeling, the poor prognosis of PPBC has been attributed to physiologic mammary gland involution, which shapes a tumor promotional microenvironment through induction of wound-healing-like programs including myeloid cell recruitment. Previous studies utilizing immune compromised mice have shown that blocking prostaglandin synthesis reduces PPBC tumor progression in a tumor cell extrinsic manner. Given the reported roles of prostaglandins in myeloid and T cell biology, and the established importance of these immune cell populations in dictating tumor growth, we investigate the impact of involution on shaping the tumor immune milieu and its mitigation by ibuprofen in immune competent hosts.

METHODS:
In a syngeneic (D2A1) orthotopic Balb/c mouse model of PPBC, we characterized the impact of mammary gland involution and ibuprofen treatment on the immune milieu in tumors and draining lymph nodes utilizing flow cytometry, multiplex IHC, lipid mass spectroscopy and cytokine arrays. To further investigate the impact of ibuprofen on programming myeloid cell populations, we performed RNA-Seq on in vivo derived mammary myeloid cells from ibuprofen treated and untreated involution group mice. Further, we examined direct effects of ibuprofen through in vitro bone marrow derived myeloid cell cultures.

RESULTS:
Tumors implanted into the mammary involution microenvironment grow more rapidly and display a distinct immune milieu compared to tumors implanted into glands of nulliparous mice. This milieu is characterized by increased presence of immature monocytes and reduced numbers of T cells and is reversed upon ibuprofen treatment. Further, ibuprofen treatment enhances Th1 associated cytokines as well as promotes tumor border accumulation of T cells. Safety studies demonstrate ibuprofen does not impede gland involution, impact subsequent reproductive success, nor promote auto-reactivity as detected through auto-antibody and naïve T cell priming assays.

CONCLUSIONS:
Ibuprofen administration during the tumor promotional microenvironment of the involuting mammary gland reduces overall tumor growth and enhances anti-tumor immune characteristics while avoiding adverse autoimmune reactions. In sum, these studies implicate beneficial prophylactic use of ibuprofen during the pro-tumorigenic window of mammary gland involution.

KEYWORDS:
Ibuprofen; Macrophages; Multiplex IHC; NSAIDs; Postpartum breast cancer; T cells; Tumor microenvironment

PMID: 30285905 PMCID: PMC6167844 DOI: 10.1186/s40425-018-0406-y
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150.
BMJ Open. 2018 Oct 2;8(10):e022069. doi: 10.1136/bmjopen-2018-022069.
Association of Meniere's disease and retinal vascular calibre: a prospective observational study in China.
Wang Y1, Diao T1, Han L1, Tao Y2, Yu L1.
Author information
1
Department of Otolaryngology, Head and Neck Surgery, People's Hospital, Peking University, Beijing, China.
2
Department of Ophthalmology, People's Hospital, Peking University, Beijing, China.
Abstract
OBJECTIVE:
It is believed that Meniere's disease (MD) is associated with vascular disorders, but few studies have reported the relationship between retinal vascular disorders and MD. We evaluated and compared the retinal vascular calibres in patients with MD with healthy subjects matched for age, sex and vascular risk factors using retinal photographs to explore the association between MD and retinal vascular calibre.

STUDY DESIGN:
A prospective study.

SETTING:
Tertiary referral centre.

PARTICIPANTS:
Sixty patients with MD and 62 healthy subjects matched for age, sex and vascular risk factors were enrolled in this study. Twenty-four patients with MD had migraines, and 36 patients with MD did not have migraines.

MAIN OUTCOME MEASURE:
Retinal vascular calibres were calculated and compared not only between patients with MD and healthy subjects but also between subgroups of patients with MD.

RESULTS:
Compared with healthy subjects, patients with MD had a slightly larger retinal artery calibre (126.30±10.45vs 119.61±15.86, p=0.006) and a higher retinal artery/vein ratio (0.79±0.09vs 0.75±0.10, p=0.005). Among patients with MD, those with migraines had a larger retinal artery calibre (130.73±11.55vs 123.35±8.61, p=0.006) than those without migraines. Moreover, the presence of migraines and the high frequency of vertigo attacks appeared to increase the retinal artery calibre.

CONCLUSIONS:
Our study suggests that a relationship exists between retinal vascular calibre and MD. Although the pathophysiological relationship between migraine and MD remains unclear, the presence of migraine attacks may aggravate endolymphatic hydrops (EH) and accelerate the outflow of EH in patients with MD. More extensive studies are required to explore the association between retinal vascular calibre and MD.

© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

KEYWORDS:
adult otolaryngology; medical retina; neurotology

PMID: 30282681 PMCID: PMC6169750 DOI: 10.1136/bmjopen-2018-022069
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Select item 30252610
151.
Otolaryngol Head Neck Surg. 2019 Jan;160(1):11-21. doi: 10.1177/0194599818800477. Epub 2018 Sep 25.
Evidence-Based Medicine in Otolaryngology Part 9: Valuing Health Outcomes.
Caulley L1,2,3, Hunink MG4,5, Kilty S2,3, Metha V6, Scangas G7, Rodin D8,9, Randolph G7, Shin JJ7.
Author information
1
1 Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
2
2 Department of Otolaryngology-Head and Neck Surgery, University of Ottawa, Ottawa, ON, Canada.
3
3 The Ottawa Hospital Research Institute, Ottawa, ON, Canada.
4
4 Department of Epidemiology and Department of Radiology, Erasmus MC, Rotterdam, The Netherlands.
5
5 Center for Health Decision Sciences, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.
6
6 Department of Otorhinolaryngology, Montefiore Medical Center, Bronx, New York, USA.
7
7 Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, USA.
8
8 Department of Radiation Oncology, Dana Farber/Brigham and Women's Cancer Center, Boston, Massachusetts, USA.
9
9 Department of Health Policy and Management, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.
Abstract
Decisions about resource allocation are increasingly based on value trade-offs between health outcomes and cost. This process relies on comprehensive and standardized definitions of health status that accurately measure the physical, mental, and social well-being of patients across disease states. These metrics, assessed through clinical trials, observational studies, and health surveys, can facilitate the integration of patient preferences into clinical practice. This ninth installment in the Evidence-Based Medicine in Otolaryngology Series is a practical overview of health outcome valuation, as well as the integration of both quality and quantity of life into standardized metrics for health research, program planning, and resource allocation. Tools for measuring preference-based health states, measures of effectiveness, and the application of metrics in economic evaluations are discussed.

KEYWORDS:
cost-effectiveness; quality of life; utility; validated instruments; value in health

PMID: 30252610 DOI: 10.1177/0194599818800477
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Select item 30226798
152.
Otolaryngol Head Neck Surg. 2019 Feb;160(2):326-331. doi: 10.1177/0194599818800470. Epub 2018 Sep 18.
Bronchoscopy for Pediatric Airway Foreign Body: Thirty-Day Adverse Outcomes in the ACS NSQIP-P.
Tan GX1, Boss EF1, Rhee DS2.
Author information
1
1 Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2
2 Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Abstract
OBJECTIVES:
(1) Describe outcomes of bronchoscopy with foreign body removal among children on the basis of a large standardized multi-institutional data set. (2) Identify factors associated with 30-day adverse events.

STUDY DESIGN:
Cross-sectional analysis of a US national database.

SETTING:
Public data set from the ACS NSQIP-P (American College of Surgeons National Surgical Quality Improvement Program-Pediatric) from 2012 to 2015.

SUBJECTS AND METHODS:
Children <18 years old who underwent bronchoscopy with removal of foreign body were identified. Patient demographics, comorbidities, hospitalization factors, surgical characteristics, and 30-day postoperative adverse events, including complication and readmission, were analyzed. Multivariate logistic regression identified predictive factors for postoperative complications and prolonged length of stay.

RESULTS:
A total of 275 children underwent bronchoscopic foreign body removal (n = 165 male, 60%; n = 75 nonwhite and/or Hispanic, 27%; mean age, 3.5 years [range, 0.63-17.9; median, 2.0]). Adverse events occurred among 10 children (4%). Seven had pulmonary-related complications, and 1 patient died. Three patients were readmitted; there were no reoperations. On multivariate analysis, preoperative pulmonary disease or need for pulmonary support (odds ratio [OR], 6.42; P = .04) predicted postoperative complications. Preoperative pulmonary compromise (OR, 8.10; P < .01), American Society of Anesthesiologists class 3 or 4 (OR, 4.13; P < .01), and prolonged operative time (OR, 3.05; P = .01) were associated with prolonged hospital stay.

CONCLUSION:
Bronchoscopy for retrieval of foreign body among children has an overall low incidence of 30-day adverse events. Children with preoperative pulmonary compromise have a significantly higher risk of postoperative complications. These findings may be applied to optimize perioperative care and counsel parents and families.

KEYWORDS:
NSQIP; adverse events; bronchoscopy; outcomes; pediatric foreign body aspiration

PMID: 30226798 DOI: 10.1177/0194599818800470
[Indexed for MEDLINE]
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153.
Otolaryngol Head Neck Surg. 2019 Jan;160(1):172-181. doi: 10.1177/0194599818800288. Epub 2018 Sep 18.
Drug-Induced Sleep Computed Tomography-Directed Upper Airway Surgery for Obstructive Sleep Apnea: A Pilot Study.
Lee LA1,2, Wang CJ2,3, Lo YL2,4, Huang CG5,6, Kuo IC1,2, Lin WN1,2, Hsin LJ1,2, Fang TJ1,2, Li HY1,2.
Author information
1
1 Department of Otorhinolaryngology-Head and Neck Surgery, Sleep Center, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
2
2 Faculty of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
3
3 Department of Medical Imaging and Intervention, Sleep Center, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
4
4 Department of Thoracic Medicine, Sleep Center, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
5
5 Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
6
6 Department of Medical Biotechnology and Laboratory Science, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
Abstract
OBJECTIVE:
A surgical response to upper airway (UA) surgery for obstructive sleep apnea (OSA) depends on adequate correction of collapsible sites in the UA. This pilot study aimed to examine the surgical response to UA surgery directed by drug-induced sleep computed tomography (DI-SCT) for OSA.

STUDY DESIGN:
Prospective case series.

SETTING:
Tertiary referral center.

SUBJECTS AND METHODS:
This study recruited 29 OSA patients (median age, 41 years; median body mass index, 26.9 kg/m2) who underwent single-stage DI-SCT-directed UA surgery between October 2012 and September 2014. DI-SCT was performed with propofol for light sedation with a bispectral monitor before and after UA surgery. Nonresponders were defined as those with a reduction in apnea-hypopnea index <50% after 6 months following UA surgery.

RESULTS:
DI-SCT showed that 28 (97%) patients had collapses at multiple sites, all of whom underwent multilevel UA surgery accordingly. The apnea-hypopnea index decreased from 53.6 to 26.8 ( P < .001). There were 18 (62%) nonresponders and 11 (38%) responders. Multiple-site collapses could not predict surgical response ( P > .99). The nonresponders had significant improvements in velopharyngeal, oropharyngeal lateral wall, and tongue collapses (all P < .05), whereas the responders had significant improvements in velopharyngeal and oropharyngeal lateral wall collapses (both P ≤ .05).

CONCLUSION:
Despite multilevel OSA surgery, residual UA obstruction in nonresponders likely occurs due to multiple mechanisms. DI-SCT may help to elucidate the reasons for a nonresponse.

KEYWORDS:
computed tomography; drug-induced sleep; obstructive sleep apnea; outcome; upper airway surgery

PMID: 30226110 DOI: 10.1177/0194599818800288
[Indexed for MEDLINE]
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Select item 30206680
154.
J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2018 Oct;204(9-10):835-847. doi: 10.1007/s00359-018-1286-9. Epub 2018 Sep 11.
Vestibular-related eye movements in the rat following selective electrical stimulation of the vestibular sensors.
Hitier M1,2,3,4, Sato G5, Zhang YF6, Zheng Y4,7,8, Besnard S3, Smith PF9,10,11.
Author information
1
Department of Otolaryngology Head and Neck Surgery, CHU de Caen, Caen, France.
2
Department of Anatomy, UNICAEN, Normadie University, 14032, Caen, France.
3
UNICAEN, University of Normandy, INSERM U1075, CHU de Caen, Caen, France.
4
Department of Pharmacology and Toxicology, School of Biomedical Sciences and Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
5
Department of Otolaryngology, University of Tokushima School of Medicine, Tokushima, Japan.
6
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
7
Brain Research New Zealand Centre of Research Excellence, Auckland, New Zealand.
8
Eisdell Moore Centre for Hearing and Balance Research, University of Auckland, Auckland, New Zealand.
9
Department of Pharmacology and Toxicology, School of Biomedical Sciences and Brain Health Research Centre, University of Otago, Dunedin, New Zealand. paul.smith@otago.ac.nz.
10
Brain Research New Zealand Centre of Research Excellence, Auckland, New Zealand. paul.smith@otago.ac.nz.
11
Eisdell Moore Centre for Hearing and Balance Research, University of Auckland, Auckland, New Zealand. paul.smith@otago.ac.nz.
Abstract
Rats are the most commonly used species in the neurosciences; however, little is known about the effects of selective electrical stimulation of individual vestibular sensors, on their eye movements. This limits their use to study the effects of vestibular stimulation on the brain, and their use in further exploring novel technologies such as artificial vestibular implants. We describe the effects of electrical stimulation of each vestibular sensor on vestibular-related eye movement in rats and compared the results to other species. We demonstrated that each sensor is responsible for specific bilateral eye movements. We found that the eye movements in rats differed from other species. Although the results were similar when stimulating the horizontal canal ampulla, differences appeared when stimulating the vertical canal sensors. During utricular stimulation, the ipsilateral eye moved dorsally in most cases, while the contralateral eye usually moved either caudally, or in extorsion. Saccular stimulation usually moved the ipsilateral eye dorsally or ventrally, while the contralateral eye usually moved ventrally or caudally. This study provides the first data on the application of selective electrical vestibular stimulation in the rat to the study of vestibular-related eye movements.

KEYWORDS:
Eye movements; Rat; Selective vestibular stimulation; Vestibular system; Vestibulo-ocular reflexes

PMID: 30206680 DOI: 10.1007/s00359-018-1286-9
[Indexed for MEDLINE]
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Select item 30200810
155.
Otolaryngol Head Neck Surg. 2019 Jan;160(1):36-48. doi: 10.1177/0194599818797598. Epub 2018 Sep 11.
Assessment and Treatment of Behavioral Disorders in Children with Hearing Loss: A Systematic Review.
Bigler D1, Burke K1, Laureano N2, Alfonso K2, Jacobs J3, Bush ML2.
Author information
1
1 College of Medicine, University of Kentucky, Lexington, Kentucky, USA.
2
2 Department of Otolaryngology-Head and Neck Surgery, University of Kentucky Medical Center, Lexington, Kentucky, USA.
3
3 Department of Health, Behavior and Society, College of Public Health, University of Kentucky Medical Center, Lexington, Kentucky, USA.
Abstract
OBJECTIVE:
There is evidence that children who are deaf and hard of hearing (DHH) have a higher incidence of behavioral disorders. Assessment of behavioral health in this population is often complicated by language developmental delays, which may result in unrecognized and untreated behavioral problems. The purpose of this study is to assess the association of behavioral disorders among children who are DHH and to explore behavioral interventions for children in this population.

DATA SOURCES:
PubMed, CINALH, PsychINFO, and Web of Science.

REVIEW METHODS:
Search terms included the following: problem behavior, child behavior disorders/diagnosis, child behavior disorders/psychology coupled with hearing loss, cochlear implants, hearing aids, or deafness. Studies from the last 30 years (1985-2016) were included. The articles were reviewed independently by 3 reviewers.

RESULTS:
Thirty-six articles met criteria. There was an association between internalizing behaviors and hearing loss among children, which may persist after cochlear implantation. These problems may be more pronounced for children with additional disabilities. Conduct and hyperactivity disorders as well as emotional and executive function problems among children who are DHH may be related to poor language development. There was limited evidence regarding interventions to address the behavioral disorders of DHH children.

CONCLUSIONS:
There is a significant body of evidence demonstrating behavioral problems among DHH children but a lack of clear understanding of the mechanisms involved. There is limited evidence on interventions to address the behavioral problems of DHH children. Future research is warranted to mitigate the long-term effects of disruptive behavior among these children.

KEYWORDS:
behavioral disorders; cochlear implants; hearing loss; systematic review

PMID: 30200810 PMCID: PMC6441325 [Available on 2020-01-01] DOI: 10.1177/0194599818797598
[Indexed for MEDLINE]
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Select item 30126331
156.
Otolaryngol Head Neck Surg. 2019 Jan;160(1):8-10. doi: 10.1177/0194599818797091. Epub 2018 Aug 21.
Cultivating and Recruiting Future Otolaryngology Residents: Shaping the Tributary.
Chang CWD1, Gray ST2,3, Malekzadeh S4, Dobratz EJ5, Schaitkin BM6, Teng MS7, Thorne MC8, Abaza MM9.
Author information
1
1 Department of Otolaryngology-Head and Neck Surgery, University of Missouri, Columbia, Missouri, USA.
2
2 Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, USA.
3
3 Department of Otolaryngology, Massachusetts Eye and Ear, Boston, Massachusetts, USA.
4
4 Department of Otolaryngology-Head and Neck Surgery, Georgetown University Medical Center, Washington, DC, USA.
5
5 Department of Otolaryngology-Head and Neck Surgery, Eastern Virginia Medical School, Norfolk, Virginia, USA.
6
6 Department of Otolaryngology-Head and Neck Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
7
7 Department of Otolaryngology-Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
8
8 Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, USA.
9
9 Department of Otolaryngology, School of Medicine, University of Colorado, Aurora, Colorado, USA.
Abstract
The future vibrancy, relevancy, and strength of our specialty depend on cultivating a pipeline of resident otolaryngologists who embody what our society wishes to become. In attracting, seeking, and nourishing physicians of all stripes, we offer several considerations regarding medical student education and the residency selection process.

KEYWORDS:
application; characteristics; education; medical students; otolaryngology; pipeline; residency; resident selection

PMID: 30126331 DOI: 10.1177/0194599818797091
[Indexed for MEDLINE]
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157.
Sleep Med. 2018 Nov;51:7-8. doi: 10.1016/j.sleep.2018.06.002. Epub 2018 Jun 27.
Rapid maxillary expansion in pediatric patients with obstructive sleep apnea: current and future perspectives.
Machado AJ Júnior1, Crespo AN2, Pauna HF2.
Author information
1
Department of Otorhinolaryngology, Head and Neck Surgery, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil. Electronic address: almiromachadophd@gmail.com.
2
Department of Otorhinolaryngology, Head and Neck Surgery, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
PMID: 30077017 DOI: 10.1016/j.sleep.2018.06.002
[Indexed for MEDLINE]
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Select item 30053749
158.
Sleep Med. 2018 Nov;51:1-6. doi: 10.1016/j.sleep.2018.05.021. Epub 2018 Jun 4.
The influence of body mass on long-term cognitive performance of children treated for sleep-disordered breathing.
Kohler M1, Kennedy D2, Martin J3, Coussens S4, Pamula Y3, Wabnitz D5, Lushington K4.
Author information
1
School of Psychology, Social Work and Social Policy, University of South Australia, Adelaide, Australia; School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, Australia. Electronic address: mark.kohler@unisa.edu.au.
2
School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, Australia; Department of Respiratory and Sleep Medicine, Women's and Children's Hospital, North Adelaide, Australia.
3
Department of Respiratory and Sleep Medicine, Women's and Children's Hospital, North Adelaide, Australia.
4
School of Psychology, Social Work and Social Policy, University of South Australia, Adelaide, Australia.
5
Department of Paediatric Otolaryngology - Head and Neck Surgery, Women's and Children's Hospital, North Adelaide, Australia.
Abstract
BACKGROUND:
Long-term follow-up of children treated for sleep-disordered breathing (SDB) is limited, as the examination of factors potentially contributing to recovery is also limited. This study aimed to examine whether the recovery of neurocognitive function is achieved at four years post-adenotonsillectomy for SDB in children and whether body mass status influences the outcome.

METHODS:
This prospective longitudinal study of 3- to 12-year-old children recruited from an otolaryngology clinic compared cognitive performance, sleep, ventilation, and body mass before and at four years post-adenotonsillectomy in children with SDB and compared these parameters to those of untreated healthy controls during the same time points.

RESULTS:
Children were categorised as normal-weight control (n = 33), normal-weight SDB (n = 18), or overweight/obese SDB (n = 11). Body mass did not significantly differ at four year follow-up compared to the baseline in any subgroup (p > 0.05), and groups were matched on the basis of age and gender. Despite improved sleep and nocturnal ventilation at four years post-adenotonsillectomy, little gain was observed in neurocognitive performance in either nonobese or overweight/obese children with SDB. Overweight/obese children with SDB displayed worse neurocognitive performance than all other children.

CONCLUSION:
Adenotonsillectomy improves nocturnal ventilation and sleep quality but not neurocognitive performance in the long term. Excess body mass may place children with SDB at increased risk of neurocognitive performance deficits.

Copyright © 2018 Elsevier B.V. All rights reserved.

KEYWORDS:
Adenotonsillectomy; Body mass; Children; Cognition; Obesity; Sleep-disordered breathing

PMID: 30053749 DOI: 10.1016/j.sleep.2018.05.021
[Indexed for MEDLINE]
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Select item 29895629
159.
Oncologist. 2018 Oct;23(10):1230-1235. doi: 10.1634/theoncologist.2018-0094. Epub 2018 Jun 12.
Pattern and Predictors of Outpatient Palliative Care Referral Among Thoracic Medical Oncologists.
Hui D1, Kilgore K2, Park M3, Liu D3, Kim YJ2,4, Park JC2,5, Fossella F6, Bruera E2.
Author information
1
Department of Palliative Care, Rehabilitation and Integrative Medicine, Houston, Texas, USA dhui@mdanderson.org.
2
Department of Palliative Care, Rehabilitation and Integrative Medicine, Houston, Texas, USA.
3
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
4
Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
5
Division of Hematology-Oncology, Department of Internal Medicine, Daejeon St. Mary's Hospital, The Catholic University of Korea, Daejeon, Republic of Korea.
6
Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Abstract
BACKGROUND:
There is significant variation in access to palliative care. We examined the pattern of outpatient palliative care referral among thoracic medical oncologists and identified oncologist characteristics associated with greater referral.

MATERIALS AND METHODS:
We retrieved data on all patients who died of advanced thoracic malignancies at our institution between January 1, 2007, and December 31, 2012. Using median as a cutoff, we defined two groups (high-referring and low-referring oncologists) based on their frequency of referral. We examined various oncologist- and patient-related characteristics associated with outpatient referral.

RESULTS:
Of 1,642 decedents, 444 (27%) had an outpatient palliative care referral. The median proportion of referral among 26 thoracic oncologists was 30% (range 9%-45%; median proportion of high-referring 37% vs. low-referring 24% when divided into two groups at median). High-referring oncologists were significantly younger (age 45 vs. 56) than low-referring oncologists; they were also significantly more likely to refer patients earlier (median interval between oncology consultation and palliative care consultation 90 days vs. 170 days) and to refer those without metastatic disease (7% vs. 2%). In multivariable mixed-effect logistic regression, younger oncologists (odds ratio [OR] = 0.97 per year increase, 95% confidence interval [CI] 0.95-0.995), younger patients (OR = 0.98 per year increase, 95% CI 0.97-0.99), and nonmetastatic disease status (OR = 0.48, 95% CI 0.29-0.78) were significantly associated with outpatient palliative care referral.

CONCLUSION:
The pattern of referral to outpatient palliative care varied widely among thoracic oncologists. Younger oncologists were not only referring a higher proportion of patients, but also referring patients earlier in the disease trajectory.

IMPLICATIONS FOR PRACTICE:
This retrospective cohort study found that younger thoracic medical oncologists were significantly more likely to refer patients to outpatient palliative care and to do so earlier in the disease trajectory compared with older oncologists, even after adjusting for other known predictors such as patient demographics. The findings highlight the role of education to standardize palliative care access and imply that outpatient palliative care referral is likely to continue to increase with a shifting oncology workforce.

© AlphaMed Press 2018.

KEYWORDS:
Ambulatory care; Health knowledge, attitudes, practice; Health services research; Neoplasms; Palliative care; Referral and consultation

PMID: 29895629 PMCID: PMC6263132 DOI: 10.1634/theoncologist.2018-0094
[Indexed for MEDLINE] Free PMC Article
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Conflict of interest statement
Publication types, MeSH terms, Grant support
Select item 29875267
160.
J Neurosci. 2018 Jul 4;38(27):6145-6160. doi: 10.1523/JNEUROSCI.3818-16.2018. Epub 2018 Jun 6.
α2δ-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses.
Kerov V1, Laird JG2, Joiner ML1, Knecht S3, Soh D1, Hagen J1, Gardner SH2, Gutierrez W4, Yoshimatsu T3, Bhattarai S5, Puthussery T6, Artemyev NO1, Drack AV5, Wong RO3, Baker SA7,5, Lee A8,9,10.
Author information
1
Department of Molecular Physiology and Biophysics.
2
Department of Biochemistry.
3
Department of Biological Structure, University of Washington, Seattle, Washington 98195, and.
4
Medical Scientist Training Program.
5
Department of Ophthalmology and Institute for Vision Research.
6
Casey Eye Institute, Oregon Health & Science University, Portland, Oregon 97239.
7
Department of Biochemistry, amy-lee@uiowa.edu sheila-baker@uiowa.edu.
8
Department of Molecular Physiology and Biophysics, amy-lee@uiowa.edu sheila-baker@uiowa.edu.
9
Department of Otolaryngology-Head and Neck Surgery.
10
Department of Neurology, University of Iowa, Iowa City, Iowa 52242.
Abstract
α2δ-4 is an auxiliary subunit of voltage-gated Cav1.4 L-type channels that regulate the development and mature exocytotic function of the photoreceptor ribbon synapse. In humans, mutations in the CACNA2D4 gene encoding α2δ-4 cause heterogeneous forms of vision impairment in humans, the underlying pathogenic mechanisms of which remain unclear. To investigate the retinal function of α2δ-4, we used genome editing to generate an α2δ-4 knock-out (α2δ-4 KO) mouse. In male and female α2δ-4 KO mice, rod spherules lack ribbons and other synaptic hallmarks early in development. Although the molecular organization of cone synapses is less affected than rod synapses, horizontal and cone bipolar processes extend abnormally in the outer nuclear layer in α2δ-4 KO retina. In reconstructions of α2δ-4 KO cone pedicles by serial block face scanning electron microscopy, ribbons appear normal, except that less than one-third show the expected triadic organization of processes at ribbon sites. The severity of the synaptic defects in α2δ-4 KO mice correlates with a progressive loss of Cav1.4 channels, first in terminals of rods and later cones. Despite the absence of b-waves in electroretinograms, visually guided behavior is evident in α2δ-4 KO mice and better under photopic than scotopic conditions. We conclude that α2δ-4 plays an essential role in maintaining the structural and functional integrity of rod and cone synapses, the disruption of which may contribute to visual impairment in humans with CACNA2D4 mutations.SIGNIFICANCE STATEMENT In the retina, visual information is first communicated by the synapse formed between photoreceptors and second-order neurons. The mechanisms that regulate the structural integrity of this synapse are poorly understood. Here we demonstrate a role for α2δ-4, a subunit of voltage-gated Ca2+ channels, in organizing the structure and function of photoreceptor synapses. We find that presynaptic Ca2+ channels are progressively lost and that rod and cone synapses are disrupted in mice that lack α2δ-4. Our results suggest that alterations in presynaptic Ca2+ signaling and photoreceptor synapse structure may contribute to vision impairment in humans with mutations in the CACNA2D4 gene encoding α2δ-4.

Copyright © 2018 the authors 0270-6474/18/386146-16$15.00/0.

KEYWORDS:
Ca2+ channel; photoreceptor; retina; ribbon synapse; synaptogenesis

PMID: 29875267 PMCID: PMC6031576 DOI: 10.1523/JNEUROSCI.3818-16.2018