In-frame deletion of SPECC1L microtubule association domain results in gain-of-function phenotypes affecting embryonic tissue movement and fusion events.

Patients with autosomal dominant SPECC1L variants show syndromic malformations, including hypertelorism, cleft palate and omphalocele. These SPECC1L variants largely cluster in the second coiled-coil domain (CCD2), which facilitates association with microtubules. To study SPECC1L function in mice, we first generated a null allele (Specc1lΔEx4) lacking the entire SPECC1L protein. Homozygous mutants for these truncations died perinatally without cleft palate or omphalocele. Given the clustering of human variants in CCD2, we hypothesized that targeted perturbation of CCD2 may be required. Indeed, homozygotes for in-frame deletions involving CCD2 (Specc1lΔCCD2) resulted in exencephaly, cleft palate and ventral body wall closure defects (omphalocele). Interestingly, exencephaly and cleft palate were never observed in the same embryo. Further examination revealed a narrower oral cavity in exencephalic embryos, which allowed palatal shelves to elevate and fuse despite their defect. In the cell, wild-type SPECC1L was evenly distributed throughout the cytoplasm and colocalized with both microtubules and filamentous actin. In contrast, mutant SPECC1L-ΔCCD2 protein showed abnormal perinuclear accumulation with diminished overlap with microtubules, indicating that SPECC1L used microtubule association for trafficking in the cell. The perinuclear accumulation in the mutant also resulted in abnormally increased actin and non-muscle myosin II bundles dislocated to the cell periphery. Disrupted actomyosin cytoskeletal organization in SPECC1L CCD2 mutants would affect cell alignment and coordinated movement during neural tube, palate and ventral body wall closure. Thus, we show that perturbation of CCD2 in the context of full SPECC1L protein affects tissue fusion dynamics, indicating that human SPECC1L CCD2 variants are gain-of-function.

SPECC1L regulates palate development downstream of IRF6.

SPECC1L mutations have been identified in patients with rare atypical orofacial clefts and with syndromic cleft lip and/or palate (CL/P). These mutations cluster in the second coiled-coil and calponin homology domains of SPECC1L and severely affect the ability of SPECC1L to associate with microtubules. We previously showed that gene-trap knockout of Specc1l in mouse results in early embryonic lethality. We now present a truncation mutant mouse allele, Specc1lΔC510, that results in perinatal lethality. Specc1lΔC510/ΔC510 homozygotes showed abnormal palate rugae but did not show cleft palate. However, when crossed with a gene-trap allele, Specc1lcGT/ΔC510 compound heterozygotes showed a palate elevation delay with incompletely penetrant cleft palate. Specc1lcGT/ΔC510 embryos exhibit transient oral epithelial adhesions at E13.5, which may delay shelf elevation. Consistent with oral adhesions, we show periderm layer abnormalities, including ectopic apical expression of adherens junction markers, similar to Irf6 hypomorphic mutants and Arhgap29 heterozygotes. Indeed, SPECC1L expression is drastically reduced in Irf6 mutant palatal shelves. Finally, we wanted to determine if SPECC1L deficiency also contributed to non-syndromic (ns) CL/P. We sequenced 62 Caucasian, 89 Filipino, 90 Ethiopian, 90 Nigerian and 95 Japanese patients with nsCL/P and identified three rare coding variants (p.Ala86Thr, p.Met91Iso and p.Arg546Gln) in six individuals. These variants reside outside of SPECC1L coiled-coil domains and result in milder functional defects than variants associated with syndromic clefting. Together, our data indicate that palate elevation is sensitive to deficiency of SPECC1L dosage and function and that SPECC1L cytoskeletal protein functions downstream of IRF6 in palatogenesis.

Beyond VOTE: The New Frontier of Drug-Induced Sleep Endoscopy.

Alternatives to positive airway pressure therapy, including surgery, represent an important area of research. Specifically, predictors of response to surgical therapy remain underdeveloped. Drug-induced sleep endoscopy (DISE) holds promise as a diagnostic tool to identify patient-specific causes of airway collapse. Herein, we present a novel, standardized approach which combines anatomic and physiologic measurements during DISE. Our DISE platform measures airflow, airway compliance, airway collapsibility, and structural drivers of collapse. Taken together, these inputs provide a comprehensive framework to further inform the surgeon in providing personalized care of the patient with obstructive sleep apnea.

The Effect of Surgical Therapy for Obstructive Sleep Apnea on Blood Pressure and Peripheral Arterial Tonometry.

OBJECTIVE: To determine the effect of upper airway surgery on cardiovascular function in patients with obstructive sleep apnea (OSA). STUDY DESIGN: A prospective, self-controlled study from 2018 to 2023. SETTING: Two academic medical centers. METHODS: Seventy-four patients underwent surgery for OSA, including: tonsillectomy, adenoidectomy, epiglottidectomy, modified uvulopalatopharyngoplasty, maxillary expansion, and maxillomandibular advancement. Twenty-four-hour ambulatory blood pressure (BP), peripheral arterial tonometry (PAT)-based home sleep study, and sleep-related patient-reported outcomes (PROs) were captured preoperatively and at 6 months postoperatively. Paired T-tests evaluated changes in outcomes after surgery. RESULTS: Forty-one patients successfully completed preoperative and postoperative assessments. Patients were generally middle-aged (43.8 ± 12.5 years), obese (BMI 33.0 ± 5.8 kg/m2), male (68%), White (71%), and had severe OSA (apnea-hypopnea index [AHI] 33.9 ± 29.5 events/h). The 4% oxygen desaturation index (ODI) decreased from 30.7 ± 27.1 to 12.2 ± 13.6 events/h (P < .01) after surgery. There was no significant difference in 24-h BP following surgery, though clinically meaningful reductions in nocturnal systolic (-1.95 [-5.34, 1.45] mmHg) and nocturnal diastolic (-2.30 [-5.11, 0.52] mmHg) blood pressure were observed. Stratified analysis showed patients undergoing skeletal surgery (n = 17) demonstrated larger average reductions compared to those undergoing soft tissue surgery in nocturnal systolic (-4.12 [-7.72, -0.51] vs -0.10 [-5.78, 5.58] mmHg) and nocturnal diastolic (-3.94 [-7.90, 0.01] vs -0.90 [-5.11, 3.31] mmHg) pressures. No meaningful changes were observed in PAT Autonomic Index (PAI) measurements. CONCLUSION: Surgical therapy for OSA did not demonstrate statistically significant improvements in 24-h BP. However, clinically meaningful reductions in nocturnal BP were observed, particularly in skeletal surgery patients, supporting the need for larger studies of cardiovascular outcomes following OSA surgery.

Airway Collapsibility during Drug-Induced Sleep Endoscopy Relates with Clinical Features of Obstructive Sleep Apnea.

INTRODUCTION: Increased pharyngeal collapsibility leads to obstructive sleep apnea (OSA). Positive airway pressure titration during drug-induced sleep endoscopy (DISE-PAP) provides objective collapsibility metrics, the pharyngeal opening pressure (PhOP), and active pharyngeal critical pressure (PcritA ). We examined the interrelationships between risk factors of OSA, airway collapsibility measures, and clinical manifestations of the disease. METHODS: This is a cross-sectional analysis of consecutive OSA patients undergoing DISE-PAP. Nasal PAP was increased stepwise until inspiratory flow limitation was abolished, signifying PhOP. PcritA was derived from the resulting titration pressure-flow relationships. Clinical data including demographics, anthropometrics, sleep studies, and patient-symptom questionnaires were obtained from the electronic medical record. Multivariate regression was used to evaluate the relationship between risk factors, airway collapsibility, and clinical data. RESULTS: On average, the 164 patients meeting inclusion criteria were middle-aged (54.2 ± 14.7 years), overweight/obese (BMI 29.9 ± 4.5 kg/m2 ), male (72.6%), White (79.3%) and had severe OSA (AHI 32.0 ± 20.5 events/hour). Mean PhOP was 7.5 ± 3.3 cm H2 O and mean PcritA was 0.80 ± 3.70 cm H2 O. Younger age (Standardized ß = -0.191, p = 0.015) and higher BMI (Standardized ß = 0.176, p = 0.028) were associated with higher PhOP, but not PcritA . PhOP and PcritA were both associated with AHI, supine AHI, and SpO2 nadir. Higher PhOP was associated with higher snoring scores (Standardized ß = 0.246, p = 0.008), but not other patient-reported outcomes. CONCLUSION: Objective assessment of passive and active airway mechanics during DISE relates with clinical risk factors for OSA. Quantitative measures of collapsibility provide accessible and meaningful data, enhancing the standard sleep surgery evaluation. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:1978-1985, 2024.

Pharyngeal Manometry and Upper Airway Collapse During Drug-Induced Sleep Endoscopy.

Importance: Drug-induced sleep endoscopy (DISE) is used to guide therapeutic management of obstructive sleep apnea (OSA), depending on the levels and patterns of pharyngeal collapse. However, the collapsibility of specific pharyngeal sites remains unknown. Objective: To assess collapse sites in patients with OSA undergoing DISE and whether number and location are associated with differences in airway collapsibility; and to quantify differences in collapsibility between primary and secondary sites in multilevel collapse. Design, Setting, and Participants: This cohort study assessed adult patients (≥18 years) with OSA undergoing DISE with manometry and positive airway pressure (PAP) titration at a tertiary care center from November 2021 to November 2023. Patients with an AHI score greater than 5 were included; those with less than 1 apnea event during DISE or incorrect catheter placement were excluded. Data were analyzed from September 28, 2022, to March 31, 2024. Exposure: DISE with manometry and PAP titration. Main Outcomes and Measures: Active pharyngeal critical pressure (Pcrit-A) and pharyngeal opening pressure (PhOP) were used to quantify airway collapsibility, adjusted for covariates (age, sex, race, and body mass index [BMI]). Results: Of 94 screened, 66 patients (mean [SD] age, 57.4 [14.3] years; BMI, 29.2 [3.9]; 51 [77.3%] males) with a mean (SD) apnea-hypopnea index (AHI) of 31.6 (19.0) were included in the analysis. Forty-seven patients (71.2%) had multilevel collapse, 10 (15.2%) had single-level nasopalatal collapse, and 9 (13.6%) had single-level infrapalatal collapse. Groups did not differ in demographic characteristics or established measures of OSA severity. The single-level nasopalatal group had substantially elevated levels of airway collapsibility (Pcrit-A and PhOP covariate adjusted mean, 2.4; 95% CI, 1.1 to 3.8; and 8.2; 95% CI, 6.4 to 9.9 cmH2O) compared to the single-level infrapalatal group (-0.9; 95% CI, -2.4 to 0.5 cmH2O; and 4.9; 95% CI, 3.0 to 6.8 cmH2O, respectively) and similar to the level among the multilevel group (1.3; 95% CI, 0.7 to 2.0; and 8.5; 95% CI, 7.7 to 9.3 cmH2O). The multilevel group had more negative inspiratory pressure (-24.2; 95% CI, -28.1 to -20.2 cmH2O) compared to the single-level nasopalatal group (-9.8; 95% CI, -18.3 to -1.28 cmH2O). In patients with multilevel collapse, airway collapsibility was significantly higher at the primary nasopalatal compared to secondary infrapalatal site (mean difference, 13.7; 95% CI, 11.3 to 16.1 cmH2O). Conclusions and Relevance: The findings of this cohort study suggest that intervention should target the primary site of pharyngeal collapse, and secondary sites only if they are nearly as collapsible as the primary site. Future work is needed to precisely define the difference in primary and secondary collapsibility that necessitates multilevel treatment.

Hypoglossal Nerve Stimulation and Cardiovascular Outcomes for Patients With Obstructive Sleep Apnea: A Randomized Clinical Trial.

Importance: Sham-controlled trials are needed to characterize the effect of hypoglossal nerve stimulation (HGNS) therapy on cardiovascular end points in patients with moderate-severe obstructive sleep apnea (OSA). Objective: To determine the effect of therapeutic levels of HGNS, compared to sham levels, on blood pressure, sympathetic activity, and vascular function. Design, Setting, and Participants: This double-blind, sham-controlled, randomized crossover therapy trial was conducted from 2018 to 2022 at 3 separate academic medical centers. Adult patients with OSA who already had an HGNS device implanted and were adherent and clinically optimized to HGNS therapy were included. Participants who had fallen asleep while driving within 1 year prior to HGNS implantation were excluded from the trial. Data analysis was performed from January to September 2022. Interventions: Participants underwent a 4-week period of active HGNS therapy and a 4-week period of sham HGNS therapy in a randomized order. Each 4-week period concluded with collection of 24-hour ambulatory blood pressure monitoring (ABPM), pre-ejection period (PEP), and flow-mediated dilation (FMD) values. Main Outcomes and Measures: The change in mean 24-hour systolic blood pressure was the primary outcome, with other ABPM end points exploratory, and PEP and FMD were cosecondary end points. Results: Participants (n = 60) were older (mean [SD] age, 67.3 [9.9] years), overweight (mean [SD] body mass index, calculated as weight in kilograms divided by height in meters squared, 28.7 [4.6]), predominantly male (38 [63%]), and had severe OSA at baseline (mean [SD] apnea-hypopnea index, 33.1 [14.9] events/h). There were no differences observed between active and sham therapy in 24-hour systolic blood pressure (mean change on active therapy, -0.18 [95% CI, -2.21 to 1.84] mm Hg), PEP (mean change on active therapy, 0.11 [95% CI, -5.43 to 5.66] milliseconds), or FMD (mean change on active therapy, -0.17% [95% CI, -1.88% to 1.54%]). Larger differences between active and sham therapy were observed in a per-protocol analysis set (n = 20) defined as experiencing at least a 50% reduction in apnea-hypopnea index between sham and active treatment. Conclusions and Relevance: In this sham-controlled HGNS randomized clinical trial, mean 24-hour systolic blood pressure and other cardiovascular measures were not significantly different between sham and active HGNS therapy. Several methodologic lessons can be gleaned to inform future HGNS randomized clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT03359096.

Association Between Soft Tissue Measures From Computed Tomography and Upper Airway Collapsibility on Drug-Induced Sleep Endoscopy.

OBJECTIVE: Positive airway pressure (PAP) titration during drug-induced sleep endoscopy (DISE) provides objective measures of upper airway collapsibility. While skeletal measurements relate to collapsibility measures on DISE, the influence of soft tissue dimensions on upper airway collapsibility is not known. We analyzed the relationship of measures of upper airway soft tissue volumes, specifically soft palate, pharyngeal lateral walls, and tongue, with metrics of collapsibility. STUDY DESIGN: Cross-sectional analysis from a prospective cohort. SETTING: Academic medical center. METHODS: Patients seeking PAP alternative therapies for obstructive sleep apnea (OSA) underwent standardized supine computed tomography (CT) acquisition and DISE protocols. The CT analysis primarily focused on soft tissue volumes and, secondarily, on airway and skeletal volumetric measures. DISE with PAP administration (DISE-PAP) enabled the determination of the pressure at which inspiratory airflow first commenced (pharyngeal critical pressure, PcritA) and the pressure at which inspiratory flow limitation was abolished (pharyngeal opening pressure, PhOP). Both unadjusted and adjusted correlation analyses were performed to understand the relationship between upper airway anatomy and either PcritA or PhOP. RESULTS: One hundred thirty-nine subjects completed both CT and DISE-PAP. On average, patients were male (70.5%), white (84.2%), middle-aged (56.6 ± 13.5 years), and overweight (29.6 ± 4.7 kg/m2), with moderate-severe apnea-hypopnea index (29.7 ± 21.3 events/h). Adjusted for age, sex, body mass index, and skeletal volumes, soft palate, and lateral pharyngeal wall volumes were not associated with PhOP or PcritA, but a larger tongue was associated with more positive PhOP (⍴ = 0.20, P = .02), and more positive PcritA (⍴ = 0.16, P = .07). Exploratory analyses revealed smaller minimum cross-sectional retropalatal area and intramandibular volume were also associated with increased collapsibility measures. CONCLUSION: After controlling for clinical factors and skeletal volume, greater tongue volume was associated with more severe collapsibility during DISE. These results, in concert with previous work, suggest that greater tongue volume in a smaller skeletal dimensions contribute to the severity of airway collapsibility, a key driver of OSA pathogenesis.

The Accuracy and Reliability of Visually Assessed Pharyngeal Opening Pressures During Drug-Induced Sleep Endoscopy.

OBJECTIVE: To examine the accuracy and interrater reliability of a visually assessed vs airflow-based measure of pharyngeal collapsibility obtained in patients with obstructive sleep apnea undergoing drug-induced sleep endoscopy (DISE). STUDY DESIGN: Prospective observational study. SETTING: Academic tertiary care practice. METHODS: Patients underwent DISE with airflow monitoring and nasal positive airway pressure titration to determine visual and airflow-based levels of pharyngeal opening pressure (PhOP). Visual DISE-PhOP was assessed by 2 blinded independent raters and defined as the pressure at which visual confirmation of airway collapse, including snoring, was abolished. Airflow-based DISE-PhOP was defined as the minimally effective positive airway pressure that abolished inspiratory flow limitation. Equivalence testing between visual and airflow DISE-PhOP of each rater was performed with the two one sided T-test (TOST) with an a priori equivalence bound of ±1 cm H2 O. Interrater reliability was evaluated with the intraclass correlation coefficient. RESULTS: One hundred patients were enrolled in the study and 77 completed the full evaluation. The population was predominantly male (74%) with an average age of 54.8 years, body mass index of 30.1 kg/m2 , and apnea-hypopnea index of 30.7 events/h. Equivalence testing showed that both raters were within ±1 cm H2 O of airflow-based DISE-PhOP (-0.43 to 0.09 cm H2 O and -0.32 to 0.48 cm H2 O). Interrater reliability of visual DISE-PhOP between the raters was also good to excellent with an intraclass correlation coefficient of 0.895 (95% CI, 0.84-0.932). CONCLUSION: DISE-PhOP, a measure of upper airway collapsibility, was equivalent between airflow-based and visual assessments with strong interrater reliability, supporting its adoption as a standardized objective parameter in clinical DISE.

Transverse Maxillary Deficiency Predicts Increased Upper Airway Collapsibility during Drug-Induced Sleep Endoscopy.

OBJECTIVE: To examine the relationship between craniofacial skeletal anatomy and objective measures of pharyngeal collapse obtained during drug-induced sleep endoscopy. We hypothesized that transverse maxillary deficiency and an increased pharyngeal length will be associated with higher levels of pharyngeal collapsibility. STUDY DESIGN: Cross-sectional analysis in a prospective cohort. SETTING: University Hospital. METHODS: A cross-sectional analysis was conducted in a cohort of consecutive patients from the positive airway pressure (PAP) alternatives clinic who underwent computed tomography (CT) analysis and drug-induced sleep endoscopy for characterization of upper airway collapsibility. PAP titration was used to determine pharyngeal critical pressure (PCRIT ) and pharyngeal opening pressure (PhOP). CT metrics included: Transverse maxillary dimensions (interpremolar and intermolar distances) and pharyngeal length (posterior nasal spine to hyoid distance). RESULTS: The cohort (n = 103) of severe obstructive sleep apnea (Apnea and Hipopnea Index 32.1 ± 21.3 events/h) was predominantly male (71.8%), Caucasian (81.6%), middle-aged (54.4 ± 14.3 years), and obese (body mass index [BMI] = 30.0 ± 4.9 kg/m2 ). Reduced transverse maxillary dimensions were associated with higher PCRIT (intermolar distance: ß [95% confidence interval, CI] = -.25 [-0.14, -0.36] cmH2 O/mm; p = .03) and PhOP (Interpremolar distance: ß = -.25 [-0.14, -0.36] cmH2 O/mm; p = .02). Longer pharyngeal length was also associated with higher PCRIT (ß = .11 [0.08, 0.14] cmH2 O/mm, p = .04) and PhOP (ß [95% CI] = .06 [0.03, 0.09] cmH2 O/mm, p = .04). These associations persisted after adjustments for sex, age, height, and BMI. CONCLUSION: Our results further the concept that skeletal restriction in the transverse dimension and hyoid descent are associated with elevations in pharyngeal collapsibility during sleep, suggesting a role of transverse deficiency in the pathogenesis of airway obstruction.

Periprosthetic distal femur fractures treated by retrograde intramedullary nails with a 10-degree distal bend achieve significantly better post-operative radiographic alignment when compared to conventional retrograde nails.

INTRODUCTION: Periprosthetic distal femur fractures (PPDFFs) are a common complication after total knee arthroplasty (TKA). In the setting of well-fixed TKA components, treatment options include retrograde intramedullary nailing (rIMN) or lateral locked plating. Treatment with rIMN has historically been associated with potential for extension deformity when using conventional nails. We hypothesized that the PPDFFs treated with an intramedullary nail with a specifically designed 10-degree distal bend for periprosthetic fractures would result in improved post-operative sagittal alignment compared to conventional intramedullary nails. MATERIALS AND METHODS: The study was conducted at a level-1 trauma center over a 12-year period (2010 - 2022). Patients over the age of 18 who sustained a PPDFF treated with rIMN were identified. The primary outcomes of the study were post-operative coronal and sagittal alignment determined by reviewing post-operative radiographs. RESULTS: A total of 50 patients were included. Twenty-three patients were treated with a rIMN with a 10° distal bend. Twenty-seven patients were treated with a rIMN with distal bend of 5° The mean aPDFA for the 10° distal bend group was 81.7° compared to 92.8° in the 5° distal bend group (p<0.001). There were 3/23 (13%) significant sagittal plane deformities the 10° distal bend group compared to 11/27 (41%) in the 5° distal bend group (p = 0.03). There was one patient with a post-operative extension deformity in the 10° distal bend group compared to 11 patients in the 5° distal bend group (p = 0.02). CONCLUSION: Retrograde intramedullary nailing of PPDFF with a 10° distal bend results in significantly better alignment in the sagittal plane when compared to a conventional 5° nail. The use of a 5° nail resulted in an extension deformity significantly more frequently. We therefore recommend the utilization of a rIMN with a 10° distal bend when treating PPDFFs. SUMMARY: Periprosthetic distal femur fractures are a common complication following total knee arthroplasty. While several studies report on the use of retrograde intramedullary nails in the treatment of periprosthetic distal femur fractures, there are limited reports of the use of a novel retrograde intramedullary nail with a 10° distal bend in the treatment of these injuries. Herein we present a radiographic study comparing coronal and sagittal postoperative alignment following treatment with retrograde intramedullary nails with a 10° distal bend versus conventional retrograde nails with a 5° distal bend.

Enhanced drug-induced sleep endoscopy: Distinguishing central from obstructive apnea.

This case report describes a patient originally diagnosed with obstructive sleep apnea (OSA) who was later found to have central sleep apnea (CSA) during drug-induced sleep endoscopy, which was subsequently confirmed on an in-laboratory sleep study. The revised diagnosis resulted in a change in recommended therapy from hypoglossal nerve stimulation to phrenic nerve stimulation. This case report is a reminder that the sleep surgeon must be cognizant of the possibility of CSA being misclassified as OSA especially as home sleep studies become increasingly routine, and discusses ways to more easily distinguish between CSA and OSA. Laryngoscope, 133:706-708, 2023.

Influence of apnea vs hypopnea predominance in predicting mean therapeutic positive airway pressures among patients with obstructive sleep apnea.

STUDY OBJECTIVES: Lower therapeutic positive airway pressure (PAP) levels are associated with improved response to non-PAP therapies in the treatment of obstructive sleep apnea. The aim of this study was to evaluate the prevailing notion that patients with apnea-predominant obstructive sleep apnea require higher therapeutic PAP levels compared to patients with hypopnea-predominant obstructive sleep apnea. METHODS: An institutional review board-approved retrospective review was performed using strict inclusion criteria: presence of type I or III sleep study, apnea-hypopnea index > 10 events/h, and adherence to auto-adjusting continuous positive airway pressure. Patients were stratified by apnea (> 50% apneas) or hypopnea (≤ 50% apneas) predominance, and PAP data were compared. Statistical analyses were performed using Student's t test and linear regression modeling. RESULTS: Between January 1, 2018 and January 1, 2020, 500 patients met inclusion criteria. Two hundred twenty-one (44.1%) patients were apnea-predominant and 279 (55.8%) were hypopnea-predominant. Apnea-predominant patients had a slightly greater mean PAP (9.01 vs 8.36, P = .002) than hypopnea-predominant patients. Univariable and multivariable linear regression of 7 variables (obstructive apnea percentage, age, sex, body mass index, apnea-hypopnea index, O2 nadir, mask type) showed obstructive apnea percentage was the weakest predictor of therapeutic PAP levels. CONCLUSIONS: Apnea-predominant individuals demonstrated a clinically insignificant difference in PAP level compared to hypopnea-predominant individuals; moreover, obstructive apnea percentage was not a strong predictor of therapeutic PAP levels. Of the modeled variables, the strongest predictor of PAP level was apnea-hypopnea index. Further studies are needed to explore these relationships as well as additional variables that may contribute to predicting therapeutic PAP levels. CITATION: Yu JL, Liu Y, Tangutur A, et al. Influence of apnea vs hypopnea predominance in predicting mean therapeutic positive airway pressures among patients with obstructive sleep apnea. J Clin Sleep Med. 2021;17(11):2171-2178.

Clinical Radiographic Predictors of Response to Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea.

OBJECTIVE: To determine if clinically acquired cephalometric measurements, specifically soft palate size, can predict hypoglossal nerve stimulation outcomes. STUDY DESIGN: Combined prospective cohort study and retrospective review. SETTING: US sleep otolaryngology training program. METHODS: Adults with obstructive sleep apnea and apneahypopnea index greater than 15 events/h who underwent hypoglossal nerve stimulation. Eligible subjects had diagnostic preoperative sleep studies and full-night efficacy postoperative studies for analysis. Lateral neck x-rays were obtained as part of routine clinical care and measured for key cephalometric variables by trained head and neck radiologists. Continuous variables were compared using the Student t test, while χ2 testing was used for categorical variables. RESULTS: Fifty-one patients met all study criteria. On average, patients were white, middle aged, and overweight. Following hypoglossal nerve stimulation, the overall cohort achieved a significant apnea-hypopnea index reduction from 36.7 events/h to 20.6 events/h (P < .01) and a response rate of 47% (defined as apnea-hypopnea index reduction >50% and apnea-hypopnea index <20 events/h). On average, therapy responders had significantly thinner soft palates than nonresponders (13.4 ± 3.8 mm vs 16.0 ± 3.4 mm, P = .045). CONCLUSIONS: Patient-specific anatomic factors, specifically soft palate thickness, may help identify optimal candidates for hypoglossal nerve stimulation. A larger, prospective study including both anatomic and physiologic variables is required to validate these findings.

Anti-epileptic drug topiramate upregulates TGFß1 and SOX9 expression in primary embryonic palatal mesenchyme cells: Implications for teratogenicity.

Topiramate is an anti-epileptic drug that is commonly prescribed not just to prevent seizures but also migraine headaches, with over 8 million prescriptions dispensed annually. Topiramate use during pregnancy has been linked to significantly increased risk of babies born with orofacial clefts (OFCs). However, the exact molecular mechanism of topiramate teratogenicity is unknown. In this study, we first used an unbiased antibody array analysis to test the effect of topiramate on human embryonic palatal mesenchyme (HEPM) cells. This analysis identified 40 differentially expressed proteins, showing strong connectivity to known genes associated with orofacial clefts. However, among known OFC genes, only TGFß1 was significantly upregulated in the antibody array analysis. Next, we validated that topiramate could increase expression of TGFß1 and of downstream target phospho-SMAD2 in primary mouse embryonic palatal mesenchyme (MEPM) cells. Furthermore, we showed that topiramate treatment of primary MEPM cells increased expression of SOX9. SOX9 overexpression in chondrocytes is known to cause cleft palate in mouse. We propose that topiramate mediates upregulation of TGFß1 signaling through activation of γ-aminobutyric acid (GABA) receptors in the palate. TGFß1 and SOX9 play critical roles in orofacial morphogenesis, and their abnormal overexpression provides a plausible etiologic molecular mechanism for the teratogenic effects of topiramate.

SPECC1L-deficient primary mouse embryonic palatal mesenchyme cells show speed and directionality defects.

Cleft lip and/or palate (CL/P) are common anomalies occurring in 1/800 live-births. Pathogenic SPECC1L variants have been identified in patients with CL/P, which signifies a primary role for SPECC1L in craniofacial development. Specc1l mutant mouse embryos exhibit delayed palatal shelf elevation accompanied by epithelial defects. We now posit that the process of palate elevation is itself abnormal in Specc1l mutants, due to defective remodeling of palatal mesenchyme. To characterize the underlying cellular defect, we studied the movement of primary mouse embryonic palatal mesenchyme (MEPM) cells using live-imaging of wound-repair assays. SPECC1L-deficient MEPM cells exhibited delayed wound-repair, however, reduced cell speed only partially accounted for this delay. Interestingly, mutant MEPM cells were also defective in coordinated cell movement. Therefore, we used open-field 2D cultures of wildtype MEPM cells to show that they indeed formed cell streams at high density, which is an important attribute of collective movement. Furthermore, activation of the PI3K-AKT pathway rescued both cell speed and guidance defects in Specc1l mutant MEPM cells. Thus, we show that live-imaging of primary MEPM cells can be used to assess mesenchymal remodeling defects during palatal shelf elevation, and identify a novel role for SPECC1L in collective movement through modulation of PI3K-AKT signaling.

The elemental sulfur-responsive protein (SipA) from the hyperthermophilic archaeon Pyrococcus furiosus is regulated by sulfide in an iron-dependent manner.

The gene (sipA) encoding the sulfur-induced protein A (PF2025) is highly upregulated during growth of Pyrococcus furiosus on elemental sulfur (S(0)). Expression of sipA is regulated by sulfide, the product of S(0) reduction, but in an iron-dependent manner. SipA is proposed to play a role in intracellular iron sulfide detoxification.

Upper airway surgery to rescue the "untitratable" patient with OSA and obesity.

None: This is a case report of an 41-year-old male with obesity (body mass index 90 kg/m²), severe obstructive sleep apnea (OSA), and an apnea-hypopnea index of 90 events/h despite high bilevel positive airway pressure (BPAP). He presented to the PAP Alternatives Clinic and underwent tonsillectomy, expansion sphincter pharyngoplasty, and partial uvulectomy to improve positive airway pressure effectiveness. Postoperative BPAP retitration resolved the patient's OSA. The patient is currently using BPAP therapy at home with improvement in both objective and self-reported OSA outcomes.

Evaluation of Therapeutic Positive Airway Pressure as a Hypoglossal Nerve Stimulation Predictor in Patients With Obstructive Sleep Apnea.

Importance: Recent retrospective hypoglossal nerve stimulation (HGNS) outcomes data suggest that patients with low therapeutic positive airway pressure (PAP) levels achieve greater success than patients with high therapeutic PAP levels. Objective: To examine the use of therapeutic nasal PAP levels at the soft palate in predicting the outcomes of HGNS for patients with obstructive sleep apnea. Design, Setting, and Participants: This prospective cohort study used drug-induced sleep endoscopy (DISE) to evaluate the predictive capacity of therapeutic PAP levels in HGNS outcomes. In an academic sleep surgery center, 27 consecutive patients with obstructive sleep apnea who underwent DISE before implantation of an HGNS device were evaluated. The study was conducted from May 1, 2018, to June 26, 2019. Exposures: Positive airway pressure delivered through a nasal mask during DISE. Main Outcomes and Measures: Improvement in apnea-hypopnea index as measured from full-night preoperative and postoperative efficacy studies. Results: Twenty-seven patients met all inclusion criteria. The mean (SD) age was 62.0 (14.4) years, 14 participants were men (51.9%), and mean body mass index was 28.1 (4.0). Responders to HGNS therapy (n = 18) had significantly lower mean (SD) palatal opening pressure compared with nonresponders (n = 9) (5.0 [2.8] vs 9.2 [3.7] cm H2O, respectively; mean difference, -4.2; 95% CI, -6.8 to -1.6 cm H2O). After adjusting for age, sex, and body mass index, the mean palatal opening pressure value for the responders remained 3.5 cm H2O lower (95% CI, -6.7 to -0.4 cm H2O) than that of nonresponders. A palatal opening pressure cutoff level less than 8 cm H2O demonstrated a positive predictive value of 82.4%; sensitivity, 77.8%; and specificity, 66.7%. Conclusions and Relevance: In this small prospective cohort study, therapeutic nasal PAP levels during DISE differed significantly between responder and nonresponders to HGNS. Because DISE represents a mandatory, relatively standardized diagnostic tool for HGNS candidacy, the use of therapeutic nasal PAP through DISE can be broadly implemented and studied across multiple centers to possibly improve patient selection for HGNS.

Developing Traps for the Spotted Lanternfly, Lycorma delicatula (Hemiptera: Fulgoridae).

The spotted lanternfly, Lycorma delicatula (White), an invasive, phloem-feeding fulgorid generalist, was recently discovered in the United States. Current trapping methods include placing glue-covered sticky bands around trunks of host trees to exploit the lanternfly's behavior of climbing up tree trunks. These bands are messy and need to be replaced often as they become covered in both target and nontarget insects and debris. Fourth instar nymphs and adults have also shown an ability to escape from traditional tree bands or avoid capture. A promising commercially available tree band (BugBarrier) design that faces inward to the trunk and targets larger developmental stages was tested. A modified pecan weevil trap (circle trunk trap) was also compared with tree bands. This design does not require the use of insect-trapping adhesive. Circle trunk traps caught more third and fourth instar and adult L. delicatula than BugBarrier bands. Flight intercept traps caught fewer adult L. delicatula than trunk-based tree bands. In a separate comparison, more spotted lanternflies were caught on adhesive-coated 'tree mimicking' traps placed along the edges of Ailanthus altissima Swingle (Sapindales: Simaroubaceae) stands than away from hosts in an open field. Circle trunk traps are recommended for their effectiveness at capturing L. delicatula as well as their relative ease-of-use and reusability.