Acetylcholine Promotes Directionally Biased Glutamatergic Retinal Waves.

Spontaneous retinal waves are a critical driving force for the self-organization of the mouse visual system prior to eye-opening. Classically characterized as taking place in three distinct stages defined by their primary excitatory drive, Stage II waves during the first postnatal week are propagated through the volume transmission of acetylcholine while Stage III retinal waves during the second postnatal week depend on glutamatergic transmission from bipolar cells. However, both late Stage II and early Stage III retinal waves share a defining propagation bias toward the temporal-to-nasal direction despite developmental changes in the underlying cholinergic and glutamatergic retinal networks. Here, we leverage genetic and pharmacological manipulations to investigate the relationship between cholinergic and glutamatergic neurotransmission during the transition between Stage II and Stage III waves in vivo. We find that the cholinergic network continues to play a vital role in the propagation of waves during Stage III after the primary mode of neurotransmission changes to glutamate. In the absence of glutamatergic waves, compensatory cholinergic activity persists but lacks the propagation bias typically observed in Stage III waves. In the absence of cholinergic waves, gap junction-mediated activity typically associated with Stage I waves persists throughout the developmental window in which Stage III waves usually emerge and lacks the spatiotemporal profile of normal Stage III waves, including a temporal-to-nasal propagation bias. Finally, we show that cholinergic signaling through ß2 subunit-containing nicotinic acetylcholine receptors, essential for Stage II wave propagation, is also critical for Stage III wave directionality.

Identifying barriers to obstructive sleep-disordered breathing care: Parental perspectives.

OBJECTIVE: Despite established clinical practice guidelines for pediatric obstructive sleep-disordered breathing (SDB), disparities persist for this common condition. Few studies have investigated parental experiences about challenges faced in obtaining SDB evaluation and tonsillectomy for their children. To better understand parent-perceived barriers to treatment of childhood SDB, we administered a survey to assess parental knowledge of this condition. MATERIALS & METHODS: A cross-sectional survey was designed to be completed by parents of children diagnosed with SDB. Two validated surveys were administered: 1) Barriers to Care Questionnaire and 2) Obstructive Sleep-Disordered Breathing and Adenotonsillectomy Knowledge Scale for Parents. Logistic regression modeling was performed to assess for predictors of parental barriers to SDB care and knowledge. RESULTS: Eighty parents completed the survey. Mean patient age was 7.4 ± 4.6 years, and 48 (60%) patients were male. The survey response rate was 51%. Patient racial/ethnic categories included 48 (60.0%) non-Hispanic White, 18 (22.5%) non-Hispanic Black, and 14 (17.5%) Other. Parents reported challenges in the 'Pragmatic' domain, including appointment availability and cost of healthcare, as the most frequently described barrier to care. Adjusting for age, sex, race, and education, parents in the middle-income bracket ($26,500 - $79,500) had higher odds of reporting greater barriers to care than parents in the highest (>$79,500) income tier (OR 5.536, 95% CI 1.312-23.359, P = 0.020) and lowest income tier (<$26,500) (OR 3.920, 95% CI 1.096-14.020). Parents whose children had tonsillectomy (n = 40) answered only a mean 55.7% ± 13.3% of questions correctly on the knowledge scale. CONCLUSION: Pragmatic challenges were the most encountered barrier that parents reported in accessing SDB care. Families in the middle-income tier experienced the greatest barriers to SDB care compared to lower and higher income families. In general, parental knowledge of SDB and tonsillectomy was relatively low. These findings represent potential areas of improvement to target interventions to promote equitable care for SDB.

Secondary autoimmune immune ear disease (AIED): a systematic review and meta-analysis on vestibular manifestations of systemic autoimmune and inflammatory disorders.

Secondary autoimmune inner ear disease (AIED) is often bilateral and asymmetric in patients presenting with audiovestibular symptoms due to a systemic autoimmune disease. This systematic review and meta-analysis are aimed at identifying and highlighting patterns in prevalence of vestibular dysfunction, symptom presentation, and diagnostic methods in extant literature by combining clinical context from case reports with quantitative analyses from cohort studies. Screening of articles by title, abstract, and full text was completed by four reviewers (K.Z., A.L., S.C., and S.J.). In this study, we grouped secondary AIED and systemic autoimmune diseases by pathophysiologic mechanism: (1) connective tissue disease (CTD), (2) vasculitides (VAS), (3) systemic inflammatory disorders (SID), and (4) other immune-mediated disorders (OIMD). The search for AIED disease identified 120 articles (cohorts and case reports) that met the final inclusion criteria. All 120 were included in the qualitative review, and 54 articles were included for meta-analysis. Of these 54 articles, 22 included a control group (CwC). Ninety individual cases or patient presentations from 66 articles were included for analysis in addition to the 54 cohort articles. Secondary AIED does not have a diagnostic algorithm for managing vestibular symptoms. The management of audiovestibular symptoms requires close collaboration between otolaryngologists and rheumatologists to preserve end-organ function of the ear. To improve our ability to understand the impact on the vestibular system, vestibular clinicians need to develop a standardized reporting method. Clinical presentation should frequently be paired with vestibular testing to contextually investigate symptom severity and provide higher quality care.

Interrater reproducibility of the Myoton and durometer devices to quantify sclerotic chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a severe complication in long-term survivors of allogeneic hematopoietic stem cell transplantation. This disease is challenging to manage clinically due to a lack of validated tools to quantitatively measure skin sclerosis. The current gold standard for measuring skin sclerosis is the NIH Skin Score which has only moderate agreement among clinicians and experts. To more accurately assess skin sclerosis in cGVHD, the Myoton and durometer devices can be used to directly measure biomechanical parameters of the skin. However, the reproducibility of these devices is not known in patients with cGVHD. To determine this reproducibility, three observers independently measured 10 anatomic sites in each of seven patients with sclerotic cGVHD using the Myoton and durometer. Clinical reproducibility was measured by mean pairwise differences (U-statistic) and intraclass correlation coefficients (ICCs) with 95% confidence intervals (CIs). Mean pairwise differences, expressed in true physical units, were used to report typical errors for each anatomic site and device. Mean pairwise differences were less than 11% of the average overall values for all five Myoton parameters and durometer hardness. These were lower for Myoton creep (4.1%), relaxation time (4.7%), and frequency (5.1%) than decrement (9.0%), stiffness (10.4%), and durometer hardness (9.0%). Myoton parameters creep, relaxation time, and frequency showed promise for capturing skin biomechanics more accurately than Myoton stiffness, decrement, or durometer hardness. Mean pairwise differences trended highest in the shin and volar forearm and lowest in the dorsal forearm. The interobserver ICC for overall (averaged across all measured body sites of a patient) creep (0.94; 95% CI 0.87-1.00), relaxation time (0.96; 95% CI 0.90-1.00), and frequency (0.95; 95% CI 0.88-1.00), trended higher than that for decrement (0.43; 95% CI 0.00-0.88), stiffness (0.92; 95% CI 0.81-1.00), and durometer hardness (0.82; 95% CI 0.61-1.00). Similar trends were observed in healthy participants. These findings can help clinicians design better studies to assess therapeutic response to new cGVHD treatments and support the interpretation of future measurements.

Hyperspectral imaging to accurately segment skin erythema and hyperpigmentation in cutaneous chronic graft-versus-host disease.

In 51 lesions from 15 patients with the inflammatory skin condition chronic graft-versus-host-disease, hyperspectral imaging accurately delineated active erythema and post-inflammatory hyperpigmentation. The method was validated by dermatologist-approved confident delineations of only definitely affected and definitely unaffected areas in photographs. A prototype hyperspectral imaging system acquired a 2.5 × 3.5 cm2 area of skin at 120 wavelengths in the 450-850 nm range. Unsupervised extraction of unknown absorbers by endmember analysis achieved a comparable accuracy to that of supervised extraction of known absorbers (melanin, hemoglobin) by chromophore mapping: 0.78 (IQR: 0.39-0.85) vs. 0.83 (0.53-0.91) to delineate erythema and 0.74 (0.57-0.87) vs. 0.73 (0.52-0.84) to delineate hyperpigmentation. Both algorithms achieved higher specificity than sensitivity. Whereas a trained human confidently marked a median of 7% of image pixels, unsupervised and supervised algorithms delineated a median of 14% and 27% pixels. Hyperspectral imaging could overcome a fundamental practice gap of distinguishing active from inactive manifestations of inflammatory skin disease.

Systematic Review of Surgical Interventions for Inferior Turbinate Hypertrophy.

BACKGROUND: Various surgical interventions exist for treatment of inferior turbinate hypertrophy (ITH). Though mucosal-sparing techniques are generally preferred, there is lack of consensus on the optimal technique. OBJECTIVE: This systematic review sought to evaluate the evidence for treatment of bilateral nasal obstruction via inferior turbinate reduction (ITR) and provide a meta-analysis of expected results of various techniques. METHODS: PubMed, Scopus, Cochrane Library databases were queried to include articles describing surgical treatment for ITH. Exclusion criteria were concurrent nasal procedures or non-mucosal ITH. Primary outcomes included visual analog scale for nasal obstruction, nasal cavity volume by acoustic rhinometry, and resistance by anterior rhinomanometry. Subgroup analyses assessed outcomes by rhinitis diagnosis and length of follow-up, and radiofrequency ablation (RFA) was compared to microdebrider-assisted turbinoplasty (MAIT). RESULTS: A total of 1870 studies were identified with 62 meeting inclusion criteria. Reported techniques included turbinectomy, submucosal resection, RFA, MAIT, laser, or electrocautery.All techniques demonstrated significant improvements in nasal obstruction using the visual analog scale. Further comprehensive physiologic data for RFA, MAIT, and laser was available and, compared to baseline, these techniques resulted in significant improvements in nasal resistance, nasal cavity volume, and nasal airflow. Six studies directly compared RFA and MAIT with statistically similar results on VAS, nasal cavity volume, and resistance with median follow-up time of 3.5 months. Assessment of VAS congestion over time reveals peak benefit is achieved between 3-6 months follow-up. CONCLUSIONS: All reviewed ITR techniques improve patient-reported nasal obstruction. RFA and MAIT provide comparable improvements in patient-reported and physiologic nasal airflow outcomes and while benefits are sustained long-term, the peak benefit for both techniques appears to be achieved within the first year.

Outcomes and Disposition of Patients After Case Cancellation on Day of Surgery for Reasons Attributed to Medical or Anesthetic Care: A Retrospective Cohort Analysis.

BACKGROUND: Many day-of-surgery cancellations are avoidable, and different strategies are used to prevent these costly adverse events. Despite these past analyses and evaluations of positive interventions, studies have not examined the final disposition of patients whose cases were canceled in this late manner. This study sought to determine whether surgical procedures canceled for medical or anesthetic reasons were ultimately rescheduled, and the time elapsed between cancellation and completion. In addition, the resolution of the underlying issue leading to cancellation was examined. METHODS: Two years of surgical case data were reviewed in the electronic health record to isolate all procedures canceled on the intended operative date. These cases were then filtered by the documented reason for cancellation into 2 categories: 1 for cases related to medical or anesthetic care and 1 for unrelated cases. Medical- or anesthetic-related cases were further categorized to better elucidate the underlying reason for cancellation. Cases were then traced to determine if and when the procedure was ultimately completed. If a case was rescheduled, the record was reviewed to determine whether the underlying reason for cancellation was resolved. RESULTS: A total of 4472 cases were canceled in the study period with only 20% associated with medical or anesthetic causes. Of these, 72% were rescheduled and 83% of all rescheduled cases resolved the underlying issue before the rescheduled procedure. Nearly half of all cases (47.8%) canceled on the day of surgery for reasons linked to medical and/or anesthetic care were due to acute conditions. CONCLUSIONS: Nearly a fifth of cases that are canceled on the date of surgery are never rescheduled and, if they are rescheduled, the delay can be substantial. Although the majority of patients whose procedure are canceled for reasons related to medical or anesthetic care have resolved the underlying issue that led to initial postponement, a significant portion of patients have no change in their status before the ultimate completion of their surgical procedure.

Pathogenesis and Etiology of Ménière Disease: A Scoping Review of a Century of Evidence.

IMPORTANCE: Ménière disease is a rare chronic benign disorder of the inner ear with a natural history of multiple clinical phenotypes of variable severity and a tendency to burnout with time. Although multiple treatment modalities have been shown to improve the disease process-some adversely affecting cochleovestibular function-it remains uncertain whether one, several separate, or a combination of pathophysiologic mechanisms affect the disease process. A scoping review of the evidence underlying proposed pathophysiologic mechanisms of Ménière disease is needed to determine which processes are most likely to be etiopathogenic factors. OBSERVATIONS: Of the 4602 relevant articles found through Embase, Ovid, and PubMed, 444 met inclusion criteria. The most common reported causes of Ménière disease were autoimmune or immune-mediated, genetic, or structural dysfunction of the inner ear. During the study period from inception to March 2021, etiologic theories shifted from structural dysfunction to autoimmune and genetic causes of Ménière disease. CONCLUSIONS AND RELEVANCE: This scoping review found that Ménière disease is a multifactorial disease with lifelong comorbidities and loss of quality-associated life-years whose most commonly reported causes were structural dysfunction, immunologic damage, and genetic susceptibility. Recent studies have examined how autoinflammatory processes and vestibular migraine may be associated with Ménière disease. Large heterogeneity among studies may be explained by historical differences in the clinical understanding of the disease, as well as evolving intervention methodologies and practitioner expertise. Ménière disease is a multifactorial disease with lifelong comorbidities and loss of quality-associated life-years; therefore, future studies of reliable biomarkers of endolymphatic hydrops and real-time imaging are warranted to improve understanding and treatment.

Effect of Medical Therapy in Allergic Rhinitis: A Systematic Review and Meta-Analysis.

BACKGROUND: Intranasal corticosteroids (INCS), oral antihistamines (POAH), and allergen-specific immunotherapy (ASIT) are widely used in the treatment of allergic rhinitis (AR); however, appraisal of treatment effect has been heterogenous, and few studies have interpreted these outcomes in context with measures of nasal airflow. OBJECTIVE: To provide a systematic review and meta-analysis of randomized placebo-controlled trials for common therapy classes for AR to assess standardized treatment effect on validated patient-reported outcomes and physiologic measures of airflow. METHODS: A systematic search was performed in PubMed, Scopus, OVID, and Cochrane library databases to identify randomized controlled trials meeting inclusion criteria. Treatment effects of INCS, POAH, and ASIT on total nasal symptom score (TNSS), visual analog scale (VAS), Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), and peak nasal inspiratory flow (PNIF) were analyzed by meta-analysis. RESULTS: Twenty-two studies with 4673 AR patients were identified, with 5 INCS, 8 POAH, and 9 ASIT trials. INCS improved TNSS (mean difference [MD] 0.90; P = .002) and PNIF (MD 13.31 L/min [P = .0007]. POAH improved quality of life assessed by RQLQ [MD 0.36; P < .001], but no improvement was found in PNIF. ASIT improved RQLQ [MD 0.65; P < .001], with a trend toward improvement in TNSS. CONCLUSION: Overall, INCS resulted in a clinically and statistically meaningful improvement in symptom scores and physiologic measures in AR. POAH and ASIT both improved symptom scores and quality of life, but their impacts upon nasal airflow are uncertain. There is a lack of studies assessing the effect of INCS on quality of life and the effect of POAH on symptom severity, particularly for mild AR. Future studies should assess the effect of treatment for each of these patient-reported measures.

Dysfunction of the Auditory System in Children With Hypothyroidism: A Systematic Review and Meta-Analysis.

OBJECTIVE: To examine the prevalence of hearing impairment in children with hypothyroidism, and to characterize clinical and subclinical hearing loss by examining cochlear function, auditory brainstem pathways, and integration of the auditory system as a whole. DESIGN: An electronic search was conducted using PubMed, Scopus, and Cochrane Library databases. This systematic review was performed in accordance with the PRISMA guidelines. Original observational studies that utilized audiological tests for auditory system evaluations in hypothyroidism were included. A total of 2004 studies were found in the search, with 23 studies meeting the inclusion criteria. RESULTS: The pooled prevalence of hearing loss was 16.1% [95% confidence interval 10.7, 22.4] for children with congenital hypothyroidism. Hearing thresholds at pure-tone averages (0.5-2 kHz) were 1.6 dB [95% confidence interval 1.7, 4.8] higher for children with hypothyroidism compared to age-matched controls. Cochlear dysfunction was detected at middle frequencies (1-3 kHz) by otoacoustic emission testing, indicating abnormalities of hair cell function or cochlear integration. Retrocochlear involvement was detected on auditory brainstem response (ABR), with prolonged Wave I indicating a peripheral conduction abnormality localized to the middle or inner ear and eighth cranial nerve. CONCLUSIONS: Children with hypothyroidism have a higher prevalence of hearing loss than children without hypothyroidism. For children with congenital hypothyroidism, evidence of subclinical abnormalities at the level of the cochlea and eighth cranial nerve are present despite early initiation of levothyroxine therapy. Dysfunction of the auditory system might begin with predominance of peripheral conduction abnormalities early in development.

Impact of Treatment for Nasal Cavity Disorders on Sleep Quality: Systematic Review and Meta-analysis.

OBJECTIVE: To determine the impact of treatment for patients with nasal obstruction secondary to allergic rhinitis (AR) and nasal septal deviation (NSD) on sleep quality. DATA SOURCES: Primary studies were identified though PubMed, Scopus, Cochrane Library, and Web of Science. REVIEW METHODS: A systematic review was performed by querying databases for articles published through August 2020. Studies were included that reported on objective sleep parameters (apnea-hypopnea index) and sinonasal and sleep-specific patient-reported outcome measures: Rhinoconjunctivitis Quality of Life Questionnaire, Nasal Obstruction Symptom Evaluation, Epworth Sleepiness Scale (EpSS), and Pittsburgh Sleep Quality Index (PSQI). RESULTS: The database search yielded 1414 unique articles, of which 28 AR and 7 NSD studies were utilized for meta-analysis. A total of 9037 patients (8515 with AR, 522 with NSD) were identified with a mean age of 35.0 years (35.3 for AR, 34.0 for NSD). Treatment for AR and NSD significantly improved subjective sleep quality. For AR, the EpSS mean difference was -1.5 (95% CI, -2.4 to -0.5; P = .002) and for the PSQI, -1.7 (95% CI, -2.1 to -1.2; P < .00001). For NSD, the EpSS mean difference was -3.2 (95% CI, -4.2 to -2.2; P < .00001) and for the PSQI, -3.4 (95% CI, -6.1 to -0.6; P = .02). CONCLUSION: Subjective sleep quality significantly improved following treatment for AR and NSD. There were insufficient data to demonstrate that objective metrics of sleep quality similarly improved.

Phase 1A/1B dose-escalation and -expansion study to evaluate the safety, pharmacokinetics, food effects and antitumor activity of pamiparib in advanced solid tumours.

BACKGROUND: Pamiparib, a PARP1/2 inhibitor, demonstrated antitumor activity in preclinical models. METHODS: This Phase 1A/1B dose-escalation/dose-expansion study enrolled adults (≥18 years) with advanced/metastatic cancer. The dose-escalation phase evaluated the recommended Phase 2 dose (RP2D), maximum tolerated dose (MTD), and pharmacokinetics; the dose-expansion phase evaluated the antitumor activity and food effects. RESULTS: Patients (N = 101) were enrolled in dose-escalation (n = 64) and dose-expansion (n = 37). During BID dose-escalation, dose-limiting toxicities were Grade 2 nausea (n = 1, 40 mg; n = 1, 80 mg); Grade 2 nausea and Grade 2 anorexia (n = 1, 120 mg), Grade 2 nausea, Grade 3 fatigue and Grade 3 paraesthesia (n = 1, 120 mg); MTD was 80 mg BID and RP2D was 60 mg BID. Common adverse events (AEs) were nausea (69.3%), fatigue (48.5%) and anaemia (35.6%); the most common Grade ≥3 AE was anaemia (24.8%). There was a dose-proportional increase in pamiparib exposure; no food effects on pharmacokinetics were observed. In the efficacy-evaluable population (n = 77), objective response rate (ORR) was 27.3% (95% CI, 17.7-38.6%). Median duration of response was 14.9 months (95% CI, 8.7-26.3). In the epithelial ovarian cancer (EOC)-evaluable population (n = 51), ORR was 41.2% (95% CI, 27.6-55.8%). CONCLUSIONS: Pamiparib was tolerated with manageable AEs, and antitumor activity was observed in patients with EOC. CLINICALTRIALS. GOV IDENTIFIER: NCT02361723.

Subtotal Petrosectomy with Cochlear Implantation or Osseointegrated Hearing Rehabilitation: A Single Institutional Study.

OBJECTIVE: To examine audiologic outcomes and operative considerations for patients undergoing subtotal petrosectomy (STP) followed by implantable hearing restoration. STUDY DESIGN: Retrospective review. SETTING: Tertiary academic referral hospital. PATIENTS: All patients who underwent STP and implantable hearing restoration from 2014 to 2020. INTERVENTIONS: Single or staged STP with cochlear implantation (CI) or placement of an osseointegrated hearing implant (OHI). MAIN OUTCOME MEASURES: Indications for STP and CI or OHI; postoperative complication and reoperation rates; audiologic outcomes through speech recognition thresholds, AzBio sentence scores, and consonant-nucleus-consonant scores. RESULTS: Twenty-six adults (age 33-85) and six children (age 1-17) underwent 37 STP procedures with 33 CIs and four OHI. Thirty-one cases were planned single-stage, but six (16%) cases required revision surgery postoperatively due to refractory postauricular infection and breakdown of wound closure. Therefore, 25 cases were single procedures and 12 were staged. Indications for staged procedures included extensive cholesteatoma (n = 5, 42%), chronic middle ear inflammation (n = 5, 42%), and osteoradionecrosis (n = 2, 17%). No patients with OHI required revision surgery. For patients undergoing CI, the mean speech recognition thresholds improved from 80 ±â€Š21 dB to 31 ±â€Š9 dB (p < 0.001), mean aided AzBio scores improved from 11% to 43% (p = 0.002) and aided consonant-nucleus-consonant word scores improved from 6% to 47% (p < 0.001) in quiet. CONCLUSIONS: Subtotal petrosectomy is effective for creating a safe, dry ear in patients with chronic inflammation or anatomically challenging ears. Rehabilitative hearing options following STP can be achieved safely, restoring hearing to an acceptable level with CI. Careful consideration should be undertaken to approach as a single or staged procedure.

Retinal waves prime visual motion detection by simulating future optic flow.

The ability to perceive and respond to environmental stimuli emerges in the absence of sensory experience. Spontaneous retinal activity prior to eye opening guides the refinement of retinotopy and eye-specific segregation in mammals, but its role in the development of higher-order visual response properties remains unclear. Here, we describe a transient window in neonatal mouse development during which the spatial propagation of spontaneous retinal waves resembles the optic flow pattern generated by forward self-motion. We show that wave directionality requires the same circuit components that form the adult direction-selective retinal circuit and that chronic disruption of wave directionality alters the development of direction-selective responses of superior colliculus neurons. These data demonstrate how the developing visual system patterns spontaneous activity to simulate ethologically relevant features of the external world and thereby instruct self-organization.

Systematic review of measures of disease severity in rhinitis.

BACKGROUND: Rhinologists often encounter a broad spectrum of allergic rhinitis (AR) and nonallergic rhinitis (NAR) patients, who can be variably classified based upon timing and severity of disease. Our understanding of the varied quality of life (QOL) impact in different classifications of rhinitis is limited. Thus a more comprehensive understanding of the impact of rhinitis upon our patients, as measured by both patient reported outcome measures (PROMs) and clinical physiologic measures, as well as unique factors associated with disease severity is needed. METHODS: A systematic search of databases was performed to identify AR and NAR studies reporting Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), total nasal symptom score (TNSS), or visual analogue scale (VAS) scores, and physiologic measures including peak nasal inspiratory flow (PNIF) and nasal airflow. Relationships between PROMs, physiologic measures, and associated factors (e.g., allergic status, disease duration) were assessed by weighted correlations and meta-regressions. RESULTS: A total of 171 studies reporting on 33,843 patients were included. Symptoms were more severe in AR than NAR on VAS (p < 0.001). Classification based upon Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines demonstrated differences in PROM severity. There was no significant correlation between PROMs and demographic factors, comorbidities, or physiologic measures. Meta-regression identified a correlation between worse RQLQ scores and shorter disease duration (r = -0.4, p < 0.001). CONCLUSION: Rhinitic patients have more severe impact upon QOL in the presence of allergy with variable impact upon specific symptom subdomains. PROMs do not correlate with common demographic factors, comorbidities, or physiologic measures of nasal airflow.

Interobserver Variation in Evaluating Perineural Invasion for Oral Squamous Cell Carcinoma: Phase 2 Survey Study.

In a previous study, we found interobserver agreement among 88 board-certified pathologists evaluating perineural invasion (PNI) in oral squamous cell carcinoma (OSCC) was fair, and participants most often used the following criteria: (1) tumor invading the perineurium, (2) tumor surrounding a nerve. In this study, we aimed to determine whether application of these most commonly used criteria may improve interobserver agreement. 512 pathologists were invited to participate in a web-based survey. Participants were asked to assess the presence/absence of PNI in a set of OSCC photomicrographs by applying each of the two criteria above. The survey was completed by 84 board-certified pathologists [mean age: 52 years (range 31-81), mean years in practice: 19 (range 1-56)]. Interobserver agreement was moderate (k = 0.46, 95% CI 0.45-0.46) when using definition #1 (tumor invading the perineurium) and fair (k = 0.24, 95% CI 0.23-0.25) when using definition #2 (tumor surrounding a nerve). By comparison, interobserver agreement was fair (k = 0.36, 95% CI 0.35-0.37) among phase 1 participants asked to evaluate these photomicrographs as they would in their pathology practice. Differences in kappa between definition #1 and phase 1, definition #2 and phase 2, and definition #1 and #2 were statistically significant (p < 0.001). Compared to our prior study based on pathologists' personal views, the current study shows improved interobserver agreement with application of the criterion, "tumor invading the perineurium." However, further work is needed to delineate concise, objective, and more reproducible criteria for histopathologic assessment of PNI.

Photoreceptive Ganglion Cells Drive Circuits for Local Inhibition in the Mouse Retina.

Intrinsically photosensitive retinal ganglion cells (ipRGCs) exhibit melanopsin-dependent light responses that persist in the absence of rod and cone photoreceptor-mediated input. In addition to signaling anterogradely to the brain, ipRGCs signal retrogradely to intraretinal circuitry via gap junction-mediated electrical synapses with amacrine cells (ACs). However, the targets and functions of these intraretinal signals remain largely unknown. Here, in mice of both sexes, we identify circuitry that enables M5 ipRGCs to locally inhibit retinal neurons via electrical synapses with a nonspiking GABAergic AC. During pharmacological blockade of rod- and cone-mediated input, whole-cell recordings of corticotropin-releasing hormone-expressing (CRH+) ACs reveal persistent visual responses that require both melanopsin expression and gap junctions. In the developing retina, ipRGC-mediated input to CRH+ ACs is weak or absent before eye opening, indicating a primary role for this input in the mature retina (i.e., in parallel with rod- and cone-mediated input). Among several ipRGC types, only M5 ipRGCs exhibit consistent anatomical and physiological coupling to CRH+ ACs. Optogenetic stimulation of local CRH+ ACs directly drives IPSCs in M4 and M5, but not M1-M3, ipRGCs. CRH+ ACs also inhibit M2 ipRGC-coupled spiking ACs, demonstrating direct interaction between discrete networks of ipRGC-coupled interneurons. Together, these results demonstrate a functional role for electrical synapses in translating ipRGC activity into feedforward and feedback inhibition of local retinal circuits.SIGNIFICANCE STATEMENT Melanopsin directly generates light responses in intrinsically photosensitive retinal ganglion cells (ipRGCs). Through gap junction-mediated electrical synapses with retinal interneurons, these uniquely photoreceptive RGCs may also influence the activity and output of neuronal circuits within the retina. Here, we identified and studied an electrical synaptic circuit that, in principle, could couple ipRGC activity to the chemical output of an identified retinal interneuron. Specifically, we found that M5 ipRGCs form electrical synapses with corticotropin-releasing hormone-expressing amacrine cells, which locally release GABA to inhibit specific RGC types. Thus, ipRGCs are poised to influence the output of diverse retinal circuits via electrical synapses with interneurons.

Systematic Review of Negative Pressure Pulmonary Edema in Otolaryngology Procedures.

OBJECTIVE(S): Negative pressure pulmonary edema (NPPE) is a rare perioperative complication with a potentially fatal outcome. The aim of this study was to perform a systematic review of NPPE in adult otolaryngology procedures with the goal of identifying risk factors, clinical presentation, diagnosis, management and outcomes. METHODS: Systematic review performed using PubMed, Scopus, Web of Science, and Cochrane databases. RESULTS: Sixty-nine studies including data from 87 individual patients were included in this review. Fifty-six (68%) patients were male and the average patient age was 37 years old. Type 1 NPPE occurred in 63 (72%) cases, while type 2 NPPE accounted for 20 (23%) cases. The most common procedures leading to NPPE were septoplasty, rhinoplasty or sinus surgery (n = 22, 25%), directly laryngoscopy or bronchoscopy (n = 13, 15%), and tracheostomy or cricothyroidotomy (n = 11, 13%). The most employed treatment options included diuretics (n = 55, 63%) and mechanical ventilation (n = 54, 62%). Seventy-eight (90%) patients made a full recovery with an average time to NPPE resolution of 33 hours and an average length of hospitalization of 5.6 days. Five (6%) patients had a long-term morbidity and four (5%) patients died, with age and ICU stay increasing risk for death and long-term morbidity (OR 1.044 and 7.42, respectively, P < .05). CONCLUSION: Septoplasty, rhinoplasty and sinus surgery account for the majority of NPPE cases in adult otolaryngology procedures. Young, healthy patients are the most commonly involved with a slight male predominance. The vast majority of patients recover fully, however there is a significant risk for morbidity and mortality.