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ImportanceEvidence is lacking from randomized clinical trials of hypoglossal nerve stimulation in obstructive sleep apnea (OSA).ObjectiveTo evaluate the safety and effectiveness of targeted hypoglossal nerve stimulation (THN) of the proximal hypoglossal nerve in patients with OSA.Design, Setting, and ParticipantsThis randomized clinical trial (THN3) was conducted at 20 centers and included 138 patients with moderate to severe OSA with an apnea-hypopnea index (AHI) of 20 to 65 events per hour and body mass index (calculated as weight in kilograms divided by height in meters squared) of 35 or less. The trial was conducted from May 2015 through June 2018. Data were analyzed from January 2022 through January 2023.InterventionImplant with THN system; randomized 2:1 to activation at month 1 (treatment) or month 4 (control). All received 11 months of THN with follow-up at months 12 and 15, respectively.Main Outcomes and MeasuresPrimary effectiveness end points comprised AHI and oxygen desaturation index (ODI) responder rates (RRs). Treatment responses at months 4 and 12/15 were defined as a 50% or greater reduction in AHI to 20 or less per hour and an ODI decrease of 25% or greater. Coprimary end points comprised (1) month 4 AHI and ODI RR in the treatment greater than the control group and (2) month 12/15 AHI and ODI RR in the entire cohort exceeding 50%. Secondary end points included sleep apnea severity (AHI and ODI) and patient-reported outcomes (Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, and EQ-5D visual analog scale).ResultsAmong 138 participants, the mean (SD) age was 56 (9) years, and 19 (13.8%) were women. Month 4 THN RRs were substantially greater in those in the treatment vs control group (AHI, 52.3% vs 19.6%; ODI, 62.5% vs 41.3%, respectively) with treatment-control standardized mean differences of 0.725 (95% CI, 0.360-1.163) and 0.434 (95% CI, 0.070-0.843) for AHI and ODI RRs, respectively. Months 12/15 RRs were 42.5% and 60.4% for AHI and ODI, respectively. Improvements in AHI, ODI, Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, and EQ-5D visual analog scale scores were all clinically meaningful (medium to large effect size). Two serious adverse events and 100 nonserious related adverse events were observed from the implant procedure or study protocol.Conclusions and RelevanceThis randomized clinical trial found that THN demonstrated improvements in sleep apnea, sleepiness, and quality of life in patients with OSAs over an extended AHI and body mass index range without prior knowledge of pharyngeal collapse pattern. Clinically meaningful improvements in AHI and patient-reported responses compared favorably with those of distal hypoglossal nerve stimulation trials, although clinically meaningful differences were not definitive for ODI.Trial RegistrationClinicalTrials.gov Identifier: NCT02263859

1022 gene signature from RNAseq

Primary treatment for estrogen receptor-positive (ER+) breast cancer is endocrine therapy. However, substantial evidence indicates a continued role for ER signaling in tumor progression. Selective estrogen receptor degraders (SERD), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties. Furthermore, activating mutations in the ER have emerged as a resistance mechanism to current endocrine therapies. New oral SERDs with improved drug properties are under clinical investigation, but the biological profile that could translate to improved therapeutic benefit remains unclear. Here, we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradation activities against both wild-type and mutant Y537S ER. Driven by its fluoropropyl pyrrolidinyl side chain, SAR439859 has demonstrated broader and superior ER antagonist and degrader activities across a large panel of ER+ cells, compared with other SERDs characterized by a cinnamic acid side chain, including improved inhibition of ER signaling and tumor cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models, including MCF7-ESR1 wild-type and mutant-Y537S mouse tumors, and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. These findings indicate that SAR439859 may provide therapeutic benefit to patients with ER+ breast cancer, including those who have resistance to endocrine therapy with both wild-type and mutant ER.

supplemental methods, data and figures

Introduction The THN3 randomized, controlled trial of moderate to severe obstructive sleep apnea (OSA) showed that proximal (“targeted”) hypoglossal nerve stimulation (HGNS) safely improved sleep-disordered breathing (SDB) and quality of life (QOL) through 11 months of treatment. Outcomes of subjects receiving active proximal HGNS also surpassed those with inactive therapy 4 months post-implant. Herein 3-year outcomes of THN3 are reported and compared to distal HGNS (STAR trial). Methods THN3 OSA subjects (Apnea-Hypopnea Index, AHI, 20-65/hr; BMI ≤ 35 kg/m2, no drug-induced sleep endoscopy screening) were followed long-term. Complete data through 3-year follow-up were analyzed. Efficacy measures comprised AHI, Oxygen Desaturation Index (ODI), %sleep time O2 saturation < 90% (T90), Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire (FOSQ) EQ-5D Visual Analog Scale (VAS) and Snore Outcomes Survey (SOS). 36-Month medians were compared against those after 11 months of therapy (Month 12/15) and with STAR. Adverse events (AEs) during Months 12-36 for THN3 and STAR were also compared. Results 75% of THN3 participants (104/138) attended 3-year follow-up, with complete efficacy records in N≥93 except for SOS (N=67, not administered at all sites). Proximal HGNS produced clinically and statistically significant improvements in SDB and QOL at Month 12/15 that were closely maintained at 36 Months (median paired changes at Month 36 from Baseline/Month 12/15: □AHI:-18.2/-0.1, □ODI:-16.2/0.8, □T90:-1.8/0.2, □FOSQ:3.0/0.0, □ESS:-5.0/0.0, □VAS:5.0/0.0, □SOS:37.5/3.1) and were comparable to STAR at 36 Months (□AHI:-19.4, □ODI:-17.2, □T90:-1.5, □FOSQ: 2.6, □ESS:-4.0). Procedure- and device-related AEs respectively totaled (3 and 27)/(4 and 122) in THN3/STAR over Months 12-36. During this time, 3 severe related-AEs occurred in THN3; the most frequent related AEs involved tongue discomfort (N=8, device-related). Conclusion Improvements in sleep apnea and QOL on proximal HGNS at Month 12/15 persisted through at least Month 36. Proximal HGNS long-term efficacy was comparable to distal HGNS. AEs occurred uncommonly during long-term follow-up and were typically mild. Proximal HGNS is a safe, effective, stable, long-term therapy, yielding comparable improvements to distal HGNS in treating moderate to severe OSA. Results of the ongoing, confirmatory OSPREY randomized controlled trial will provide additional insights into therapeutic benefits of proximal HGNS. Support (if any) LivaNova

Hydrogen bonding phase-transfer catalysis offers a convenient solution to activate safe and economical metal alkali fluorides for enantioselective nucleophilic fluorination. Herein, we demonstrate the scalability of this protocol with the fluorination of 200 g of racemic trans-N,N-dibenzyl-2-bromocyclohexan-1-amine in a mechanically stirred 1 L glass reactor using 0.5 mol % of a bis-urea organocatalyst. In these experiments, full conversions were obtained for high mixing intensities (impeller average shear rate >10 000 s–1; maximum energy dissipation per unit of mass >300 W/kg). The thermal safety of the reaction was assessed by differential scanning calorimetry and reaction calorimetry, assigning the reaction to Stoessel’s critical class 3.

More than 75% of breast cancers are estrogen receptor alpha (ERα) positive (ER+), and resistance to current hormone therapies occurs in one-third of ER+ patients. Tumor resistance is still ERα-dependent, but mutations usually confer constitutive activation to the hormone receptor, rendering ERα modulator drugs such as tamoxifen and aromatase inhibitors ineffective. Fulvestrant is a potent selective estrogen receptor degrader (SERD), which degrades the ERα receptor in drug-resistant tumors and has been approved for the treatment of hormone-receptor-positive metastatic breast cancer following antiestrogen therapy. However, fulvestrant shows poor pharmacokinetic properties in human, low solubility, weak permeation, and high metabolism, limiting its administration to inconvenient intramuscular injections. This Drug Annotation describes the identification and optimization of a new series of potent orally available SERDs, which led to the discovery of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (43d), showing promising antitumor activity in breast cancer mice xenograft models and whose properties warranted clinical evaluation.

Introduction THN3 was the first reported parallel-arm, randomized controlled trial (RCT) of hypoglossal nerve stimulation (HGNS), wherein targeted HGNS (THN) was shown to be safe and efficacious at ameliorating sleep disordered breathing in patients with moderate to severe OSA and BMI≤35kg/m2 without screening with drug-induced sleep endoscopy. Unique among reported HGNS trials, separate cohorts of patients receiving early and late THN were followed longitudinally. Methods Measurements of apnea-hypopnea index (AHI) were available Pre-enrollment, Baseline (2 nights), Month 4 and Month 12/15. Except for Pre-enrollment, AHI values were calculated by an independent core laboratory from polysomnographic recordings. All subjects with complete data were included for analysis. AHI trajectories were constructed for early and late THN activation (Treatment[T], N=83, Month 1 and Control[C], N=45, Month 4, respectively) by computing median values. Confidence intervals were calculated by bootstrapping each median (N=30,000). Patient-reported outcome measures (PROMs) were treated similarly. Results AHI (Median (95% CI)) trajectories demonstrated a consistent pattern of pre-implant alignment (Pre-enrollment T:39.1 (36.0-45.0), C:38.0 (32.0-41.0); Baseline 1 T:36.1 (33.0-39.9), C:31.3 (27.2-38.6); Baseline 2 T:37.0 (34.3-41.0), C:35.2 (32.3-38.2)), divergence at the conclusion of the randomization period (Month 4 T:15.6 (11.9-25.3), C:30.6 (23.7-38.6)) and reconvergence following 11 months of treatment (Month 12/15 T:20.7 (16.0-26.4), C:18.1 (16.3-23.3)). Non-standardized Pre-enrollment AHI was slightly higher than Baseline values. Trajectories were similar for oxygen desaturation index (Baseline 1 T:35.3 (31.9-38.0),C:34.3 (27.5-40.3); Baseline 2 T:37.1 (33.4-39.3),C:36.8 (33.9-38.3); Month 4 T:19.5 (16.2-28.5), C:33.8 (25.4-41.1); Month 12/15 T:19.5 (16.0-25.6), C:19.7 (16.3-26.0)), the Epworth Sleepiness Scale (Baseline T:11.0 (10.0-13.0),C:11.5 (8.5-14.0); Month 4 T:6.0 (5.0-7.0), C:11.5 (8.0-12.5); Month 12/15 T:6.0 (4.0-7.0), C:5.5 (4.5-6.0)), the Functional Outcomes of Sleep Questionnaire (Baseline T:15.3 (14.0-16.5),C:14.7 (13.3-16.6); Month 4 T:18.3 (17.7-18.8), C:16.7 (14.9-17.7); Month 12/15 T:18.8 (18.3-19.3), C:18.5 (17.5-19.5)) and the Snore Outcomes Survey (Baseline T:26.6 (21.9-31.3),C:21.9 (18.8-31.3); Month 4 T:60.9 (56.3-67.9), C:29.7 (23.4-42.9); Month 12/15 T:62.5 (59.4-68.8), C:68.8 (62.5-71.9)). Conclusion Group trajectories of sleep-disordered breathing and PROMs further demonstrate the robust effects of THN in patients with moderate to severe OSA and the value of parallel-arm RCTs. Similar results may be expected in the ongoing OSPREY confirmatory trial of THN. Support (If Any) LivaNova

Introduction THN3 was the first reported parallel-arm, randomized controlled trial of hypoglossal nerve stimulation (HGNS), wherein targeted HGNS (THN) was shown to be safe and efficacious at ameliorating sleep disordered breathing in selected patients with moderate to severe OSA and BMI≤35kg/m2 without screening with drug-induced sleep endoscopy. A secondary THN3 objective was to identify baseline characteristics which enhance therapeutic response. Methods Predictors of long-term (Month 12/15) apnea-hypopnea index (AHI) response (reduction ≥50% to ≤20/hr) were identified in stages. Baseline characteristics, including polysomnography parameters, were screened one at a time using univariate logistic regression. Variables significant at α=0.25 were further selected using stepwise multivariate logistic regression. Candidate predictors were then optimized by manual, incremental threshold adjustment to maximize AHI response rate (RR). Optimized predictors were ranked according to the AHI RR and size of the corresponding subpopulation, with a goal of capturing at least 40% of the overall THN3 cohort. Results Baseline sleep efficiency (SE) in the normal range (>85%) achieved the highest AHI RR while retaining 42% (58/138) of the THN3 cohort. Similar to the overall study population, subgroup subjects were predominantly middle-aged (age 54±7 years), male (83%), Caucasian (86%) and overweight/obese (BMI 30±3 kg/m2). Short-term (Month 4) AHI RRs in the Treatment and Control groups were 59.5% and 20.0%, respectively, with long-term AHI RR at 50.9%. Median AHI was reduced from 35.1 to 16.0, as compared to 29.3 to 9.0 in the STAR trial of distal HGNS. ODI RRs (reduction ≥25%) for Treatment and Control were respectively 73.0% and 30.0% at Month 4 and 64.9% at Month12/15. Enhanced response carried through to larger point estimates for improvement in secondary variables, including the Epworth Sleepiness Scale and the Functional Outcomes of Sleep Questionnaire, exceeding minimum clinically important differences thresholds of 2-3 and 1.7-2.0, respectively. Conclusion Normal SE at Baseline was associated with enhanced AHI and ODI RR as well as patient-reported outcome measures for patients receiving THN therapy, providing results similar to those obtained with distal HGNS. Future studies, including the ongoing OSPREY trial, will be needed to prospectively validate these findings. Support (If Any) LivaNova

S-Trifluoromethyl sulfoximines and S-trifluoromethyl sulfilimino iminiums are important reagents for the electrophilic or radical late-stage introduction of the CF3 group. We disclose in this artic...

Primary treatment for estrogen receptor-positive (ER+) breast cancer is endocrine therapy. However, substantial evidence indicates a continued role for ER signaling in tumor progression. Selective estrogen receptor degraders (SERD), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties. Furthermore, activating mutations in the ER have emerged as a resistance mechanism to current endocrine therapies. New oral SERDs with improved drug properties are under clinical investigation, but the biological profile that could translate to improved therapeutic benefit remains unclear. Here, we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradation activities against both wild-type and mutant Y537S ER. Driven by its fluoropropyl pyrrolidinyl side chain, SAR439859 has demonstrated broader and superior ER antagonist and degrader activities across a large panel of ER+ cells, compared with other SERDs characterized by a cinnamic acid side chain, including improved inhibition of ER signaling and tumor cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models, including MCF7-ESR1 wild-type and mutant-Y537S mouse tumors, and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. These findings indicate that SAR439859 may provide therapeutic benefit to patients with ER+ breast cancer, including those who have resistance to endocrine therapy with both wild-type and mutant ER.

The purpose of the present study is to review the international literature, using a systematic review, for studies comparing propofol and dexmedetomidine for drug-induced sleep endoscopy (DISE) or sedation in which there is a description of the effect of the agents on the upper airway and associated variables (e.g., vital signs, sedation scores). This is a systematic review through October 4, 2016. PubMed/MEDLINE and four additional databases were accessed for this study. Two hundred twenty studies were screened, 79 were downloaded, and 10 met criteria. The majority of the studies identified dexmedetomidine as the preferred pharmacologic agent for DISE due to an overall safer and more stable profile based upon hemodynamic stability. However, propofol provided greater airway obstruction with oxygen desaturations. With either agent, the degree of obstruction in the upper airway lacks some degree of validity as to whether the obstructions accurately represent natural sleep or are simply a drug-induced effect. Dexmedetomidine and propofol have their advantages and disadvantages during DISE. Generally, dexmedetomidine was preferred and seemed to provide a more stable profile based upon cardiopulmonary status. However, propofol has a quicker onset, has a shorter half-life, and can demonstrate larger degrees of obstruction, which might more accurately reflect what happens during REM sleep. Additional research is recommended.

Objectives/Hypothesis To perform a systematic review with meta-analysis for sleep study outcomes in children who have undergone rapid maxillary expansion (RME) as treatment for obstructive sleep apnea (OSA). Data Sources PubMed/MEDLINE and eight additional databases. Review Methods Three authors independently and systematically reviewed the international literature through February 21, 2016. Results Seventeen studies reported outcomes for 314 children (7.6 ± 2.0 years old) with high-arched and/or narrow hard palates (transverse maxillary deficiency) and OSA. Data were analyzed based on follow-up duration: ≤3 years (314 patients) and >3 years (52 patients). For ≤3-year follow-up, the pre- and post-RME apnea–hypopnea index (AHI) decreased from a mean ± standard deviation (M ± SD) of 8.9 ± 7.0/hr to 2.7 ± 3.3/hr (70% reduction). The cure rate (AHI 3-year follow-up (range = 6.5–12 years), the AHI was reduced from an M ± SD of 7.1 ± 5.7/hr to 1.5 ± 1.8/hr (79% reduction). Conclusions Improvement in AHI and lowest oxygen saturation has consistently been seen in children undergoing RME, especially in the short term (

Objective To perform a systematic review and meta-analysis for studies evaluating genioplasty alone, genial tubercle advancement (GTA) alone, and GTA with hyoid surgery (GTA-HS) to treat obstructive sleep apnea (OSA). Data Sources Ten databases. Review Methods Three authors searched through November 15, 2015. Results 1,207 studies were screened; 69 were downloaded; and 13 studies met inclusion criteria. A total of 111 patients were included, with 27 standard genioplasty, 10 modified genioplasty, 24 GTA, and 50 GTA-HS patients. For standard genioplasty, the apnea-hypopnea index (AHI) reduced from a mean ± standard deviation (M ± SD) of 18.8 ± 3.8 (95% confidence interval [CI] 17.6, 20.0) to 10.8 ± 4.0 (95% CI 9.5, 12.1) events/hour (relative reduction 43.8%), P value = 0.0001. Genioplasty improved lowest oxygen saturation (LSAT) from 82.3 ± 7.3% (95% CI 80.0, 84.7) to 86.8 ± 5.2% (95% CI 85.1, 88.5), P value = 0.0032. For modified genioplasty AHI increased by 37.3%. For GTA, the AHI reduced from an M ± SD of 37.6 ± 24.2 (95% CI 27.9, 47.3) to 20.4 ± 15.1 (95% CI 14.4, 26.4) events/hour (relative reduction 45.7%), P value = 0.0049. GTA improved LSAT from 83.1 ± 8.3% (95% CI 79.8, 86.4) to 85.5 ± 6.8% (95% CI 82.8, 88.2), P value = 0.2789. For GTA-HS, the AHI reduced from an M ± SD of 34.5 ± 22.1 (95% CI 28.4, 40.6) to 15.3 ± 17.6 (95% CI 10.4, 20.2) events/hour (relative reduction 55.7%), P value < 0.0001; GTA-HS improved LSAT from 80.1 ± 16.6% (95% CI 75.5, 84.7) to 88.3 ± 6.9% (95% CI 86.4, 90.2), P value = 0.0017. Conclusion Standard genioplasty, GTA and GTA-HS can improve OSA outcomes such as AHI and LSAT. Given the low number of studies, these procedures remain as an area for additional OSA research. Laryngoscope, 127:984–992, 2017

Objective This study sought to systematically review the international literature for articles evaluating maxillary expansion and maxillomandibular expansion as treatments for obstructive sleep apnea (OSA) in adults and to perform a meta-analysis. Data sources Nine databases (including MEDLINE/PubMed). Review methods Searches were performed through January 8, 2016. The PRISMA statement was followed. Results Eight adult studies (39 patients) reported polysomnography and/or sleepiness outcomes. Six studies reported outcomes for maxillary expansion (36 patients), and the apnea-hypopnea index (AHI) decreased from a mean (M) ± standard deviation (SD) of 24.3 ± 27.5 [95% CI 15.3, 33.3] to 9.9 ± 13.7 [95% CI 5.4, 14.4] events/hr (relative reduction: 59.3%). Maxillary expansion improved lowest oxygen saturation (LSAT) from a M ± SD of 84.3 ± 8.1% [95% CI 81.7, 87.0] to 86.9 ± 5.6% [95% CI 85.1, 88.7]. Maxillomandibular expansion was reported in two studies (3 patients) and AHI decreased from a M ± SD of 47.53 ± 29.81 [95% CI −26.5 to 121.5] to 10.7 ± 3.2 [95% CI 2.8, 18.6] events/hr (relative reduction: 77.5%). Maxillomandibular expansion improved LSAT from a M ± SD of 76.7 ± 14.5% [95% CI 40.7, 112.7] to 89.3 ± 3.1 [95% CI 81.6, 97]. Conclusion The current literature demonstrates that maxillary expansion can improve and maxillomandibular expansion can possibly improve AHI and LSAT in adults; however, given the paucity of studies, these remain open for additional research efforts.

Objectives/Hypothesis To determine if sleepiness and sleep study variables (e.g., Apnea-Hypopnea Index [AHI] and lowest oxygen saturation) improve following isolated tonsillectomy for adult obstructive sleep apnea (OSA). Study Design Systematic review and meta-analysis. Methods Nine databases (PubMed/MEDLINE included) were searched through November 24, 2015. Results Seventeen studies (n = 216 patients, 34.4 ± 10.0 years and body mass index: 29.0 ± 6.1 kg/m2) met criteria. Tonsils sizes were hypertrophied, large, enlarged, extremely enlarged, or grades 2 to 4. Apnea-Hypopnea Index decreased by 65.2% (from 40.5 ± 28.9/hour to 14.1 ± 17.1/hour) (n = 203). The AHI mean difference (MD) was −30.2 per hour (95% confidence interval [CI] −39.3, −21.1) (P value < 0.00001). The AHI SMD was −1.37 (−1.65, −1.09) (large effect). Lowest oxygen saturation improved from 77.7 ± 11.9% to 85.5 ± 8.2% (n = 186). Lowest oxygen saturation MD was 8.5% (95% CI 5.2, 11.8) (P value < 0.00001). The Epworth Sleepiness Scale decreased from 11.6 ± 3.7 to 6.1 ± 3.9 (P value < 0.00001) (n = 125). Individual patient outcomes (n = 54) demonstrated an 85.2% success rate (AHI < 20/hour and ≥ 50% reduction) and a 57.4% cure rate. Individual patient data meta-analysis showed preoperative AHI < 30 per hour to be a significant predictor of surgical success (P value < 0.001) and cure (P value = 0.043); among patients with preoperative AHI < 30 per hour, tonsillectomy success rate was 100% (25 of 25) and cure rate was 84% (21 of 25) with a mean postoperative AHI of 2.4 ± 2.1 per hour; this compares to tonsillectomy success rate of 72.4% (21 of 29), cure rate of 10 of 29 (34.4%), and mean postoperative AHI of 14.3 ± 13.9 per hour for patients with preoperative AHI ≥ 30 per hour. Conclusion Isolated tonsillectomy can be successful as treatment for adult OSA, especially among patients with large tonsils and mild to moderate OSA (AHI < 30/hour). Laryngoscope, 2016 Laryngoscope, 126:2176–2186, 2016

Objectives/Hypothesis The primary objective was to determine if sleep study variables (e.g., apnea-hypopnea index [AHI] and lowest oxygen saturation) and quantitative sleepiness data improve following isolated hyoid surgery for obstructive sleep apnea (OSA). Study Design Systematic review and meta-analysis. Methods Nine databases, including PubMed, were searched through September 5, 2015. Results Four hundred ninety-eight studies were screened, 64 were reviewed, and nine studies met inclusion criteria. A total of 101 patients were identified who underwent hyoid surgery alone for treatment of OSA. Subanalyses were performed for: 1) type of surgery, 2) primary versus secondary hyoid surgery, 3) positional versus nonpositional OSA, 4) age, and 5) body mass index. In patients undergoing isolated hyoid surgery, the AHI decreased from a mean ± standard deviation of 37.3 ± 21.1 (95% confidence interval [CI]: 33.1, 41.5) to 23.0 ± 18.6 (95% CI: 19.3, 26.7) events/hour, which correspond to a 38.3% reduction (P < .0001). AHI reduced by 38.3% for hyoid myotomy with suspension, by 50.7% for hyothyroidopexy, and by 7.1% for hyoid expansion. The Epworth Sleepiness Scale decreased by 3.2 points from 10.3 ± 4.9 (95% CI: 8.8, 11.8) to 7.1 ± 4.2 (95% CI: 5.8, 8.4; P = .0027). Conclusions Isolated hyoid surgery has reduced OSA severity and improved sleepiness in adults. Hyothyroidopexy provided a 50.7% reduction in AHI, followed by hyoid myotomy with suspension (38.3% reduction in AHI) and hyoid expansion (7.1% reduction in AHI). The current literature lacks high-quality evidence with regard to hyoid surgery, and additional studies are needed to further elucidate the effect of hyoid surgery in OSA. Level of Evidence NA Laryngoscope, 2015

Objective.To systematically review the international literature for internal nasal septal deviation classification systems and summarize them for clinical and research purposes.Data Sources.Four databases (including PubMed/MEDLINE) were systematically searched through December 16, 2015.Methods.Systematic review, adhering to PRISMA.Results.After removal of duplicates, this study screened 952 articles for relevance. A final comprehensive review of 50 articles identified that 15 of these articles met the eligibility criteria. The classification systems defined in these articles included C-shaped, S-shaped, reverse C-shaped, and reverse S-shaped descriptions of the septal deviation in both the cephalocaudal and anteroposterior dimensions. Additional studies reported use of computed tomography and categorized deviation based on predefined locations. Three studies graded the severity of septal deviations based on the amount of deflection. The systems defined in the literature also included an evaluation of nasal septal spurs and perforations.Conclusion.This systematic review ascertained that the majority of the currently published classification systems for internal nasal septal deviations can be summarized by C-shaped or reverse C-shaped, as well as S-shaped or reverse S-shaped deviations in the anteroposterior and cephalocaudal dimensions. For imaging studies, predefined points have been defined along the septum. Common terminology can facilitate future research.

Objective. To search for articles evaluating the use of tracheostomies (either permanent stomas or tracheostomy tubes) in adult obstructive sleep apnea (OSA) patients and to evaluate the potential for the use of mini tracheostomies as treatment for OSA.Study Design. Systematic review.Methods. Nine databases were searched from inception through July 21, 2015.Results. The overall tracheostomy search yielded 516 articles, of which eighteen studies provided polysomnographic data. No study was identified (empty review) for the use of mini tracheostomies for treating OSA. The mini tracheostomy search yielded ninety-five articles which describe findings for either mini tracheostomy kits (inner cannula diameter of 4 mm) or the performance of mini tracheotomies. Six articles described the use of mini tracheostomies as a temporary procedure to relieve acute upper airway obstruction and none described the use for OSA. For tracheostomy stomal sites, suturing the skin directly to the tracheal rings with defatting can minimize stomal site collapse. The smallest tracheostomy stomal size that can successfully treat OSA has not been described.Conclusion. Mini tracheostomies as small as 4 mm have been successfully used in the short term to relieve upper airway obstruction. Given that polysomnography data are lacking, additional research is needed.

Objective. To develop a quick, simple, bedside test for determining continuous positive airway pressures (CPAP) for obstructive sleep apnea (OSA) patients.Study Design. Prospective case series at a tertiary medical center.Methods. The Five-Minute Awake Snoring Test for Determining CPAP (Five-Minute CPAP Test) was developed and tested. Patients wear a soft-gel nasal triangle mask while holding a tongue depressor with the wide section (1.75 cm) between the teeth. Fixed pressure nasal CPAP is applied while the patient simulates snoring at 4 centimeters of water pressure. The pressure is incrementally titrated up and then down to determine the lowest pressure at which the patient cannot snore (Quiet Pressure).Results. Overall, thirty-eight patients participated. All could simulate snoring. Correlation coefficients were statistically significant between Quiet Pressures and body mass index (rs=0.60[strong positive relationship],p=0.0088), apnea-hypopnea index (rs=0.49[moderate positive relationship],p=0.039), lowest oxygen saturation (rs=-0.47[moderate negative relationship],p=0.048), and oxygen desaturation index (rs=0.62[strong positive relationship],p=0.0057).Conclusion. This pilot study introduces a new concept, which is the final product of over one year of exploration, development, and testing. Five-Minute CPAP Test is a quick, inexpensive, and safe bedside test based on supine awake simulated snoring with nasal CPAP.

Objectives/Hypothesis To determine if apnea-hypopnea index (AHI) and lowest oxygen saturation (LSAT) improve following isolated supraglottoplasty for laryngomalacia with obstructive sleep apnea (OSA) in children. Study Design Systematic review and meta-analysis. Methods Nine databases, including PubMed/MEDLINE, were searched through September 30, 2015. Results A total of 517 studies were screened; 57 were reviewed; and 13 met criteria. One hundred thirty-eight patients were included (age range: 1 month–12.6 years). Sixty-four patients had sleep exclusive laryngomalacia, and in these patients: 1) AHI decreased from a mean (M) ± standard deviation (SD) of 14.0 ± 16.5 (95% confidence interval [CI] 10.0, 18.0) to 3.3 ± 4.0 (95% CI 2.4, 4.4) events/hour (relative reduction: 76.4% [95% CI 53.6, 106.4]); 2) LSAT improved from a M ± SD of 84.8 ± 8.4% (95% CI 82.8, 86.8) to 87.6 ± 4.4% (95% CI 86.6, 88.8); 3) standardized mean differences (SMD) demonstrated a small effect for LSAT and a large effect for AHI; and 4) cure (AHI < 1 event/hour) was 10.5% (19 patients with individual data). Seventy-four patients had congenital laryngomalacia, and in these patients: 1) AHI decreased from a M ± SD of 20.4 ± 23.9 (95% CI 12.8, 28.0) to 4.0 ± 4.5 (95% CI 2.6, 5.4) events/hour (relative reduction: 80.4% [95% CI 46.6, 107.4]); 2) LSAT improved from a M ± SD of 74.5 ± 11.9% (95% CI 70.9, 78.1) to 88.4 ± 6.6% (95% CI 86.4, 90.4); 3) SMD demonstrated a large effect for both AHI and LSAT; and 4) cure was 26.5% (38 patients with individual data). Conclusion Supraglottoplasty has improved AHI and LSAT in children with OSA and either sleep exclusive laryngomalacia or congenital laryngomalacia; however, the majority of them are not cured. Laryngoscope, 2015

Objectives Intermittent hypoxemia is a risk factor for developing complications in obstructive sleep apnea (OSA) patients. The objective of this systematic review was to identify articles evaluating the accuracy of the oxygen desaturation index (ODI) as compared with the apnea-hypopnea index (AHI) and then provide possible values to use as a cutoff for diagnosing adult OSA. Study design Systematic Review of Literature. Methods PubMed, the Cochrane Library, and SCOPUS databases were searched through November 2019. Results Eight studies (1,924 patients) met criteria (age range: 28-70.9 years, body mass index range: 21.9-37 kg/m2 , and AHI range: 0.5-62 events/hour). Five studies compared ODI and AHI simultaneously, and three had a week to months between assessments. Sensitivities ranged from 32% to 98.5%, whereas specificities ranged from 47.7% to 98%. Significant heterogeneity was present; however, for studies reporting data for a 4% ODI ≥ 15 events/hour, the specificity for diagnosing OSA ranged from 75% to 98%, and only one study reported the positive predictive value, which was 97%. Direct ODI and AHI comparisons were not made because of different hypopnea scoring, different oxygen desaturation categories, and different criteria for grading OSA severity. Conclusion Significant heterogeneity exists in studies comparing ODI and AHI. Based on currently published studies, consideration should be given for diagnosing adult OSA with a 4% ODI of ≥ 15 events/hour and for recommending further evaluation for diagnosing OSA with a 4% ODI ≥ 10 events/hour. Screening with oximetry may be indicated for the detection of OSA in select patients. Further study is needed before a definitive recommendation can be made. Laryngoscope, 131:440-447, 2021.

Objective Traditionally, upper airway examination is performed while the patient is awake. However, in the past two decades, drug-induced sleep endoscopy (DISE) has been used as a method of tridimensional evaluation of the upper airway during pharmacologically induced sleep. This study aimed to systematically review the evidence regarding the usefulness of DISE compared with that of traditional awake examination for surgical decision making in patients with obstructive sleep apnea (OSA). Data Sources Scopus, PubMed, and Cochrane Library databases were searched. Review Methods Only studies with a primary objective of evaluating the usefulness of DISE for surgical decision making in patients with OSA were selected. The included studies directly compared awake examination data with DISE outcome data in terms of possible influences on surgical decision making and operation success. Results A total of eight studies with 535 patients were included in this review. Overall, the surgical treatment changed after DISE in 50.24% (standard deviation 8.4) cases. These changes were more frequently associated with structures contributing to hypopharyngeal or laryngeal obstruction. However, these differences do not automatically indicate a higher success rate. Conclusion This review emphasized the direct impact of DISE compared with that of awake examination on surgical decision making in OSA patients. However, it is also clear that the available published studies lack evidence on the association between this impact and surgical outcomes. Laryngoscope, 2015

Objectives/Hypothesis Obstructive sleep apnea (OSA) is a syndrome frequently diagnosed in children; however, it lacks optimal diagnostic methods. This study aimed to provide a clinical decision rule for predicting pediatric OSA using commonly available clinical information. Study Design A prospective cohort study. Methods Children between the ages of 3 to 6 years-old, referred for an otorhinolaryngology consultation due to clinical suspicion of OSA, were recruited from January to June 2014. At baseline age, weight, height, gender, body mass index, Pediatric Sleep Questionnaire (PSQ) scores, tonsil size, and oxygen desaturation index (ODI) were assessed. A logistic regression modeling was used with backward stepwise elimination to develop a prediction model. Results Sixty-seven children were included with a mean age of 4.51 years. Of the 67 children included in this study, 25 (37.3%) subjects were diagnosed with pediatric OSA. Significant predictors of pediatric OSA in the final model (odds ratio, 95% confidence interval) included PSQ score (5.12; 3.3–6.5), ODI (1.34; 1.0–1.79) and tonsil size (6.7; 3.22–9.75). The final decision rule had a sensitivity of 88% and a specificity of 86%. The area under the receiver operating characteristic curve was 0.897. Conclusion The proposed clinical decision rule, based on three readily available variables, is a promising discriminating instrument for prediction of OSA among children between 3 and 6 years. Level of Evidence IIb. Laryngoscope, 2015

OBJECTIVE: To systematically review the literature for articles evaluating myofunctional therapy (MT) as treatment for obstructive sleep apnea (OSA) in children and adults and to perform a meta-analysis on the polysomnographic, snoring, and sleepiness data. DATA SOURCES: Web of Science, Scopus, MEDLINE, and The Cochrane Library. REVIEW METHODS: The searches were performed through June 18, 2014. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement was followed. RESULTS: Nine adult studies (120 patients) reported polysomnography, snoring, and/or sleepiness outcomes. The pre- and post-MT apneahypopnea indices (AHI) decreased from a mean ± standard deviation (M ± SD) of 24.5 ± 14.3/h to 12.3 ± 11.8/h, mean difference (MD) -14.26 [95% confidence interval (CI) -20.98, -7.54], P < 0.0001. Lowest oxygen saturations improved from 83.9 ± 6.0% to 86.6 ± 7.3%, MD 4.19 (95% CI 1.85, 6.54), P = 0.0005. Polysomnography snoring decreased from 14.05 ± 4.89% to 3.87 ± 4.12% of total sleep time, P < 0.001, and snoring decreased in all three studies reporting subjective outcomes. Epworth Sleepiness Scale decreased from 14.8 ± 3.5 to 8.2 ± 4.1. Two pediatric studies (25 patients) reported outcomes. In the first study of 14 children, the AHI decreased from 4.87 ± 3.0/h to 1.84 ± 3.2/h, P = 0.004. The second study evaluated children who were cured of OSA after adenotonsillectomy and palatal expansion, and found that 11 patients who continued MT remained cured (AHI 0.5 ± 0.4/h), whereas 13 controls had recurrent OSA (AHI 5.3 ± 1.5/h) after 4 y. CONCLUSION: Current literature demonstrates that myofunctional therapy decreases apnea-hypopnea index by approximately 50% in adults and 62% in children. Lowest oxygen saturations, snoring, and sleepiness outcomes improve in adults. Myofunctional therapy could serve as an adjunct to other obstructive sleep apnea treatments.

BACKGROUND The relationship between nasal surgery and its effect on continuous positive airway pressure (CPAP) device therapeutic treatment pressures and CPAP device use has not been previously systematically examined. STUDY OBJECTIVES To conduct a systematic review and meta-analysis evaluating the effect of isolated nasal surgery on therapeutic CPAP device pressures and use in adults with obstructive sleep apnea (OSA). METHODS MEDLINE, Scopus, Web of Science, and The Cochrane Library were searched through July 15, 2014. The MOOSE consensus statement and PRISMA statement were followed. RESULTS Eighteen studies (279 patients) reported CPAP data after isolated nasal surgery. Seven studies (82 patients) reported preoperative and postoperative mean therapeutic CPAP device pressures and standard deviations (SD), which reduced from 11.6 ± 2.2 to 9.5 ± 2.0 centimeters of water pressure (cwp) after nasal surgery. Pooled random effects analysis demonstrated a statistically significant pressure reduction, with a mean difference (MD) of -2.66 cwp (95% confidence interval (CI), -3.65 to -1.67); P < 0.00001. Eleven studies (153 patients) reported subjective, self-reported data for CPAP use; and a subgroup analysis demonstrated that 89.1% (57 of 64 patients) who were not using CPAP prior to nasal surgery subsequently accepted, adhered to, or tolerated it after nasal surgery. Objective, device meter-based hours of use increased in 33 patients from 3.0 ± 3.1 to 5.5 ± 2.0 h in the short term (

Objective.To quantify the effectiveness of nasal expiratory positive airway pressure (nasal EPAP) devices or Provent as treatment for obstructive sleep apnea (OSA).Methods.PubMed and six other databases were searched through November 15, 2015, without language limitations.Results.Eighteen studies (920 patients) were included. Pre- and post-nasal EPAP means ± standard deviations (M ± SD) for apnea-hypopnea index (AHI) in 345 patients decreased from27.32±22.24to12.78±16.89events/hr (relative reduction = 53.2%). Random effects modeling mean difference (MD) was −14.78 events/hr [95% CI −19.12, −10.45],pvalue < 0.00001. Oxygen desaturation index (ODI) in 247 patients decreased from21.2±19.3to12.4±14.1events/hr (relative reduction = 41.5%,pvalue < 0.00001). Lowest oxygen saturation (LSAT) M ± SD improved in 146 patients from83.2±6.8% to86.2±11.1%, MD 3 oxygen saturation points [95% CI 0.57, 5.63]. Epworth Sleepiness Scale (ESS) M ± SD improved (359 patients) from9.9±5.3to7.4±5.0, MD −2.5 [95% CI −3.2, −1.8],pvalue < 0.0001.Conclusion.Nasal EPAP (Provent) reduced AHI by 53.2%, ODI by 41.5% and improved LSAT by 3 oxygen saturation points. Generally, there were no clear characteristics (demographic factors, medical history, and/or physical exam finding) that predicted favorable response to these devices. However, limited evidence suggests that high nasal resistance could be associated with treatment failure. Additional studies are needed to identify demographic and polysomnographic characteristics that would predict therapeutic success with nasal EPAP (Provent).

Objective:To systematically review outcomes of adults with obstructive sleep apnoea treated with nasopharyngeal airway stenting devices.Methods:Medline, Scopus, Web of Science and the Cochrane Library databases were searched, and data on device use and tolerability, sleepiness, oxygen saturation, apnoea index, apnoea–hypopnoea index, and sleep quality were collected.Results:Of 573 potential studies, 29 were retrieved for detailed evaluation and 16 met the study criteria. Polysomnography data for patients treated with nasal trumpets as an isolated therapy were pooled for meta-analysis. The mean apnoea index ± standard deviation, for 53 patients, decreased from 32.4 ± 15.9 to 9.0 ± 7.2 episodes per hour (p p p Conclusion:Some studies have demonstrated limited effectiveness and low tolerability of nasopharyngeal airway stenting devices, while other studies have shown a significant benefit in treating obstructive sleep apnoea, with a high level of patient acceptance. Nasal trumpets have been successful in decreasing airway obstruction in the short term.

Objectives/Hypothesis Poor adherence to continuous positive airway pressure treatment in obstructive sleep apnea (OSA) adversely affects the effectiveness of this therapy. This study aimed to systematically review the evidence regarding the efficacy and safety of hypoglossal nerve stimulation as an alternative therapy in the treatment of OSA. Data Sources Scopus, PubMed, and Cochrane Library databases were searched (updated through September 5, 2014). Methods Studies were included that evaluated the efficacy of hypoglossal nerve stimulation to treat OSA in adults with outcomes for apnea-hypopnea index (AHI), oxygen desaturation index (ODI), and effect on daytime sleepiness (Epworth Sleepiness Scale [ESS]). Tests for heterogeneity and subgroup analysis were performed. Results Six prospective studies with 200 patients were included in this review. At 12 months, the pooled fixed effects analysis demonstrated statistically significant reductions in AHI, ODI, and ESS mean difference of −17.51 (95% CI: −20.69 to −14.34); −13.73 (95% CI: −16.87 to −10.58), and −4.42 (95% CI: −5.39 to −3.44), respectively. Similar significant reductions were observed at 3 and 6 months. Overall, the AHI was reduced between 50% and 57%, and the ODI was reduced between 48% and 52%. Despite using different hypoglossal nerve stimulators in each subgroup analysis, no significant heterogeneity was found in any of the comparisons, suggesting equivalent efficacy regardless of the system in use. Conclusions This review reveals that hypoglossal nerve stimulation therapy may be considered in selected patients with OSA who fail medical treatment. Further studies comparing hypoglossal nerve stimulation with conventional therapies are needed to definitively evaluate outcomes. Level of Evidence NA Laryngoscope, 125:1254–1264, 2015

To perform a systematic review with meta-analysis for sleep study outcomes in children who have undergone rapid maxillary expansion (RME) as treatment for obstructive sleep apnea (OSA).PubMed/MEDLINE and eight additional databases.Three authors independently and systematically reviewed the international literature through February 21, 2016.Seventeen studies reported outcomes for 314 children (7.6 ± 2.0 years old) with high-arched and/or narrow hard palates (transverse maxillary deficiency) and OSA. Data were analyzed based on follow-up duration: ≤3 years (314 patients) and3 years (52 patients). For ≤3-year follow-up, the pre- and post-RME apnea-hypopnea index (AHI) decreased from a mean ± standard deviation (M ± SD) of 8.9 ± 7.0/hr to 2.7 ± 3.3/hr (70% reduction). The cure rate (AHI1/hr) for 90 patients for whom it could be calculated was 25.6%. Random effects modeling for AHI standardized mean difference (SMD) is -1.54 (large effect). Lowest oxygen saturation (LSAT) improved from 87.0 ± 9.1% to 96.0 ± 2.7%. Random effects modeling for LSAT SMD is 1.74 (large effect). AHI improved more in children with previous adenotonsillectomy or small tonsils (73-95% reduction) than in children with large tonsils (61% reduction). For3-year follow-up (range = 6.5-12 years), the AHI was reduced from an M ± SD of 7.1 ± 5.7/hr to 1.5 ± 1.8/hr (79% reduction).Improvement in AHI and lowest oxygen saturation has consistently been seen in children undergoing RME, especially in the short term (3-year follow-up). Randomized trials and more studies reporting long-term data (≥3-year follow-up) would help determine the effect of growth and spontaneous resolution of OSA. Laryngoscope, 2016 Laryngoscope, 127:1712-1719, 2017.

Obstructive sleep apnea is a highly prevalent and poorly understood condition that not only leads to significant individual patient health damage, but carries a large societal cost secondary to excessive healthcare utilization, motor-vehicle accidents, and work absenteeism. While a significant fund of knowledge about its damaging effects on the cardiovascular system and neural pathways has been gathered over the past few decades, the translation to direct patient care still presents numerous challenges. With the exception of clear issues such as socially unacceptable snoring and breathing irregularities, the exact cause and effect relationship between airway narrowing, hypoxemia, and sleep fragmentation with subjective sleep-related complaints and neurocognitive symptoms is less clear. Besides better-defined clinical diagnostic criteria, the need for clear serum, saliva, or urine biomarkers to assess the physiologic burden of disease remains a work in progress, as are well-defined long-term clinically relevant outcomes of interest. Here, readers will be guided to a critical evaluation on the current main metrics of sleep study, suggested steps on diagnostic and treatment goals, and introduced to the concept of a continuum of disease.

Objectives/Hypothesis To develop a validated inferior turbinate grading scale. Study Design Development and validation study. Methods Phase 1 development (alpha test) consisted of a proposal of 10 different inferior turbinate grading scales (>1,000 clinic patients). Phase 2 validation (beta test) utilized 10 providers grading 27 standardized endoscopic photos of inferior turbinates using two different classification systems. Phase 3 validation (pilot study) consisted of 100 live consecutive clinic patients (n = 200 inferior turbinates) who were each prospectively graded by 18 different combinations of two independent raters, and grading was repeated by each of the same two raters, two separate times for each patient. Results In the development phase, 25% (grades 1–4) and 33% (grades 1–4) were the most useful systems. In the validation phase, the 25% classification system was found to be the best balance between potential clinical utility and ability to grade; the photo grading demonstrated a Cohen's kappa (κ) = 0.4671 ± 0.0082 (moderate inter-rater agreement). Live-patient grading with the 25% classification system demonstrated an overall inter-rater reliability of 71.5% (95% confidence interval [CI]: 64.8–77.3), with overall substantial agreement (κ = 0.704 ± 0.028). Intrarater reliability was 91.5% (95% CI: 88.7–94.3). Distribution for the 200 inferior turbinates was as follows: 25% quartile = grade 1, 50% quartile (median) = grade 2, 75% quartile = grade 3, and 90% quartile = grade 4. Mean turbinate size was 2.22 (95% CI: 2.07-2.34; standard deviation 1.02). Categorical κ was as follows: grade 1, 0.8541 ± 0.0289; grade 2, 0.7310 ± 0.0289; grade 3, 0.6997 ± 0.0289, and grade 4, 0.7760 ± 0.0289. Conclusions The 25% (grades 1–4) inferior turbinate classification system is a validated grading scale with high intrarater and inter-rater reliability. This system can facilitate future research by tracking the effect of interventions on inferior turbinates. Level of Evidence 2c Laryngoscope, 125:296–302, 2015

The objective of this study was to systematically assess the evidence for the diagnostic accuracy of unattended type 2 or type 3 multichannel studies for predicting and monitoring pediatric obstructive sleep apnea (OSA). Four medical databases were searched for eligible studies. Only studies that evaluated the ability of unattended multichannel devices to accurately diagnose or monitor OSA in children were included. Those with appropriate data were selected for meta-analysis. Study quality was assessed by using the Quality Assessment Tool for Diagnostic Accuracy Studies tool. Summary estimates of diagnostic accuracy were determined by using sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio, summary receiver operating characteristics, and the area under the curve (AUC). Ten diagnostic studies with 724 patients were included in the systematic review, which was followed by a meta-analysis using studies that provided sufficient information for the calculation of diagnostic parameters. The overall analysis revealed a moderate sensitivity of 76% (95% confidence interval [CI]: 64%-85%), a moderate specificity of 76% (95% CI: 60%-88%), and a pooled diagnostic odds ratio of 15.18 (95% CI: 3.52-65.43). The AUC (0.88) indicated that unattended multichannel devices showed good diagnostic performance for predicting pediatric OSA. Using a cutoff of AHI > 1 for the diagnosis of OSA, the results appeared to be more useful, with a higher sensitivity (88%) while maintaining a moderate specificity (71%). These findings suggest that unattended sleep studies are a good tool for predicting both the presence and severity of OSA in children, especially in those with mild-to-moderate disease.

Compelling molecular biology publications have reported the implication of phosphoinositide kinase PI3Kβ in PTEN-deficient cell line growth and proliferation. These findings supported a scientific rationale for the development of PI3Kβ-specific inhibitors for the treatment of PTEN-deficient cancers. This paper describes the discovery of 2-[2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (7) and the optimization of this new series of active and selective pyrimidone indoline amide PI3Kβ inhibitors. 2-[2-(2-Methyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (28), identified following a carefully designed methyl scan, displayed improved physicochemical and in vitro pharmacokinetic properties. Structural biology efforts enabled the acquisition of the first X-ray cocrystal structure of p110β with the selective inhibitor compound 28 bound to the ATP site. The nonplanar binding mode described herein is consistent with observed structure-activity relationship for the series. Compound 28 demonstrated significant in vivo activity in a UACC-62 xenograft model in mice, warranting further preclinical investigation. Following successful development, compound 28 entered phase I/Ib clinical trial in patients with advanced cancer.

Objectives/Hypothesis To systematically review outcomes for polysomnography, sleepiness, and mortality in patients who undergo tracheostomy for the treatment of adult obstructive sleep apnea (OSA). Data Sources MEDLINE, Scopus, and the Cochrane Library were searched from inception to March 2013, followed by extensive hand searching for the identification of relevant English language studies that met predefined criteria. Review Methods Adult studies of tracheostomies or tracheotomies as treatment for OSA with outcomes for apnea index (AI), apnea–hypopnea index (AHI), oxygen desaturation index (ODI), effect on daytime sleepiness or mortality were identified, abstracted and pooled (as appropriate). Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Results The systematic search identified 18 relevant studies that were primarily case series, using retrospective review. Posttracheostomy AI improved from 73.0 ± 27.1 to 0.2 ± 1.2/h and an AI mean difference of −83.47 (95% CI, −106.07 to −60.87; P

There is an extensive amount of literature on surgeries as treatment for obstructive sleep apnea syndrome on adults. Previous systematic reviews have been performed to summarize the outcomes for sleep surgeries, with conflicting results. The objective of this study was to critically evaluate these systematic reviews to provide an overview of their quality, strengths, and conclusions.MEDLINE, Scopus, and the Cochrane Collaboration databases were searched from inception to April 2013.An overview of systematic reviews was undertaken. Studies included in this review are the systematic reviews whose primary objective was to evaluate the outcomes of sleep apnea surgery on adults. The methodological quality of the studies was analyzed with AMSTAR checklist, and the quality of evidence was evaluated using the GRADE assessment tool. Primary outcome measures assessed the effect of surgery on snoring, sleepiness, and the apnea-hypopnea index.A total of 11 studies were included in this study, and the pooled overview includes 378 studies. The systematic reviews were mostly graded as low quality using the GRADE tool and low to moderate according to the AMSTAR checklist. Outcome for apnea-hypopnea index demonstrated substantial variation leading to conflicting results. Despite a high amount of heterogeneity, outcomes for sleepiness and snoring demonstrated significant improvement across included reviews.Although obstructive sleep apnea surgery is associated with improved outcomes in most studies, the level and quality of evidence reviews requires improvement.

Objective:To systematically search for studies reporting outcomes for adenoidectomy alone as a treatment for paediatric obstructive sleep apnoea and use the data to perform a meta-analysis.Methods:Nine databases, including PubMed and Medline, were systematically searched through to 1 April 2016. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement was followed.Results:A total of 1032 articles were screened and 126 full texts were reviewed. Three paediatric studies (47 patients) reported outcomes. Overall, apnoea–hypopnoea index values decreased from 18.1 ± 16.8 to 3.1 ± 5.5 events per hour (28 patients). Random-effects modelling demonstrated a mean difference of −14.43 events per hour (I2 = 23 per cent (low inconsistency)). The apnoea–hypopnoea index standardised mean difference was −1.14 (large magnitude of effect). The largest reduction in apnoea–hypopnoea index was observed in children aged less than 12 months (reduction of 56.6−94.9 per cent). Lowest oxygen saturation values improved from 80.0 ± 9.5 to 85.5 ± 6.0 per cent (13 children).Conclusion:Adenoidectomy alone has improved obstructive sleep apnoea in children, especially in those aged less than 12 months; however, given the low number of studies, isolated adenoidectomy remains an area for additional research.

To perform a systematic review and meta-analysis for studies evaluating genioplasty alone, genial tubercle advancement (GTA) alone, and GTA with hyoid surgery (GTA-HS) to treat obstructive sleep apnea (OSA).Ten databases.Three authors searched through November 15, 2015.1,207 studies were screened; 69 were downloaded; and 13 studies met inclusion criteria. A total of 111 patients were included, with 27 standard genioplasty, 10 modified genioplasty, 24 GTA, and 50 GTA-HS patients. For standard genioplasty, the apnea-hypopnea index (AHI) reduced from a mean ± standard deviation (M ± SD) of 18.8 ± 3.8 (95% confidence interval [CI] 17.6, 20.0) to 10.8 ± 4.0 (95% CI 9.5, 12.1) events/hour (relative reduction 43.8%), P value = 0.0001. Genioplasty improved lowest oxygen saturation (LSAT) from 82.3 ± 7.3% (95% CI 80.0, 84.7) to 86.8 ± 5.2% (95% CI 85.1, 88.5), P value = 0.0032. For modified genioplasty AHI increased by 37.3%. For GTA, the AHI reduced from an M ± SD of 37.6 ± 24.2 (95% CI 27.9, 47.3) to 20.4 ± 15.1 (95% CI 14.4, 26.4) events/hour (relative reduction 45.7%), P value = 0.0049. GTA improved LSAT from 83.1 ± 8.3% (95% CI 79.8, 86.4) to 85.5 ± 6.8% (95% CI 82.8, 88.2), P value = 0.2789. For GTA-HS, the AHI reduced from an M ± SD of 34.5 ± 22.1 (95% CI 28.4, 40.6) to 15.3 ± 17.6 (95% CI 10.4, 20.2) events/hour (relative reduction 55.7%), P value0.0001; GTA-HS improved LSAT from 80.1 ± 16.6% (95% CI 75.5, 84.7) to 88.3 ± 6.9% (95% CI 86.4, 90.2), P value = 0.0017.Standard genioplasty, GTA and GTA-HS can improve OSA outcomes such as AHI and LSAT. Given the low number of studies, these procedures remain as an area for additional OSA research. Laryngoscope, 127:984-992, 2017.

From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kβ isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kβ. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.

Objectives/Hypothesis: Clinical symptoms and signs are routinely used to investigate pediatric obstructive sleep apnea (OSA). This study aimed to systematically assess the evidence for the diagnostic accuracy of individual or combined clinical symptoms and signs in predicting pediatric OSA. Study Design: A systematic review of the literature and diagnostic meta-analysis. Methods: Four medical databases were searched (from inception to August 2011). Studies were included that compared the clinical assessment with the current gold standard (full polysomnography). The study quality was assessed using the quality assessment tool for diagnostic accuracy studies. Summary estimates of diagnostic accuracy were determined using the sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio, and hierarchical summary receiver operating characteristic (HSROC) model for meta-analyses. Results: Ten diagnostic studies with 1,525 patients were included in the review. There was substantial variation in the sensitivity and specificity among different symptoms and signs, as well as across studies. Tonsillar size and snoring reported by parents or caregivers had high sensitivity but low specificity. In contrast, excessive daytime somnolence, observed apnea, and difficulty in breathing during sleep had high specificity but low sensitivity. Seven models of a combination of symptoms and signs presented moderate sensitivity (range, 0.04–0.94) and specificity (range, 0.28–0.99). The HSROC indicates poor diagnostic performance of the symptoms and signs in predicting pediatric OSA. Conclusions: Neither single nor combined symptoms and signs have satisfactory performance in predicting pediatric OSA. Alternative diagnostic models are necessary to improve the accuracy.

Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single PI3K isoforms differentially control tumorigenesis, and PI3Kβ has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors. Herein we describe the discovery and optimization of a new series of benzimidazole- and benzoxazole-pyrimidones as small molecular mass PI3Kβ-selective inhibitors. Starting with compound 5 obtained from a one-pot reaction via a novel intermediate 1, medicinal chemistry optimization led to the discovery of compound 8, which showed a significant activity and selectivity for PI3Kβ and adequate in vitro pharmacokinetic properties. The X-ray costructure of compound 8 in PI3Kδ showed key interactions and structural features supporting the observed PI3Kβ isoform selectivity. Compound 8 achieved sustained target modulation and tumor growth delay at well tolerated doses when administered orally to SCID mice implanted with PTEN-deficient human tumor xenografts.

Maxillomandibular advancement (MMA) is an invasive yet effective surgical option for obstructive sleep apnea (OSA) that achieves enlargement of the upper airway by physically expanding the facial skeletal framework.To identify criteria associated with surgical outcomes of MMA using aggregated individual patient data from multiple studies.The Cochrane Library, Scopus, Web of Science, and MEDLINE from June 1, 2014, to March 16, 2015, using the Medical Subject Heading keywords maxillomandibular advancement, orthognathic surgery, maxillary osteotomy, mandibular advancement, sleep apnea, surgical, surgery, sleep apnea syndrome, and obstructive sleep apnea.Inclusion criteria consisted of studies in all languages of (1) adult patients who underwent MMA as treatment for OSA; (2) report of preoperative and postoperative quantitative outcomes for the apnea-hypopnea index (AHI) and/or respiratory disturbance index (RDI); and (3) report of individual patient data. Studies of patients who underwent adjunctive procedures at the time of MMA (including tonsillectomy, uvulopalatopharyngoplasty, and partial glossectomy) were excluded.Three coauthors systematically reviewed the articles and updated the review through March 16, 2015. The PRISMA statement was followed. Data were pooled using a random-effects model and analyzed from July 1, 2014, to September 23, 2015.The primary outcomes were changes in the AHI and RDI after MMA for each patient. Secondary outcomes included surgical success, defined as the percentage of patients with more than 50% reduction of the AHI to fewer than 20 events/h, and OSA cure, defined as a post-MMA AHI of fewer than 5 events/h.Forty-five studies with individual data from 518 unique patients/interventions were included. Among patients for whom data were available, 197 of 268 (73.5%) had undergone prior surgery for OSA. Mean (SD) postoperative changes in the AHI and RDI after MMA were -47.8 (25.0) and -44.4 (33.0), respectively; mean (SE) reductions of AHI and RDI outcomes were 80.1% (1.8%) and 64.6% (4.0%), respectively; and 512 of 518 patients (98.8%) showed improvement. Significant improvements were also seen in the mean (SD) postoperative oxygen saturation nadir (70.1% [15.6%] to 87.0% [5.2%]; P .001) and Epworth Sleepiness Scale score (13.5 [5.2] to 3.2 [3.2]; P .001). Rates of surgical success and cure were 389 (85.5%) and 175 (38.5%), respectively, among 455 patients with AHI data and 44 (64.7%) and 13 (19.1%), respectively, among 68 patients with RDI data. Preoperative AHI of fewer than 60 events/h was the factor most strongly associated with the highest incidence of surgical cure. Nevertheless, patients with a preoperative AHI of more than 60 events/h experienced large and substantial net improvements despite modest surgical cure rates.Maxillomandibular advancement is an effective treatment for OSA. Most patients with high residual AHI and RDI after other unsuccessful surgical procedures for OSA are likely to benefit from MMA.

Nearly 70% or more of newly diagnosed cases of breast cancer (BC) are estrogen receptor positive (ER+) where endocrine therapy is a primary treatment. However, substantial evidence describes a continued role of ER signaling in tumor progression, where approximately 40% of patients on endocrine therapy develop resistance that include mutations in the ER that drive a constitutively active receptor. Fulvestrant, an estrogen receptor degrader, is effective at shutting down ER signaling. However, fulvestrant efficacy studies report insufficient blockade of ER signaling in patients that may be a consequence of poor pharmaceutical properties. Here we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradative properties against ER both in vitro and in vivo. SAR439859 has robust inhibition of ER signaling activity in multiple ER+ breast cancer cell lines including tamoxifen resistant lines harboring ER mutations. Across a large panel of ER+ cells, SAR439859 demonstrated broad and superior ER degradation activity as compared to other SERDs including improved inhibition of ER signaling and inhibition of cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ BC models including MCF7-ESR1 mutant-Y537S model and endocrine therapy resistant patient-derived xenograft tumor transplantation. Collectively, these results showed that SAR439859 is an oral, nonsteroidal, selective estrogen receptor antagonist and degrader that could provide therapeutic benefit to ER+ breast cancer patients. SAR439859 is currently being evaluated in a phase I clinical trial. Citation Format: Maysoun Shomali, Youssef El-Ahmad, Frank Halley, Jane Cheng, Michael Weinstein, Muchun Wang, Fangxian Sun, Natalia Malkova, Mikhail Levit, Malvika Koundinya, Zhuyan Gou, Andrew Hebert, Jessica McManus, Dietmar Hoffman, Hui Cao, Joonil Jung, Jack Pollard, Sylvie Vincent, Timothy Ackerson, Francisco Adrian, Chris Winter, Victoria Richon, Hong Chen, Karl Hsu, Joanne Lager, Albane Courjaud, Rosalia Arrebola, Laurent Besret, Pierre-Yves Abecassis, Laurent Schio, Gary McCort, Michel Tabart, Victor Certal, Fabienne Thompson, Bruno Filoche-Rommé, Laurent Debussche, Patrick Cohen, Carlos Garcia-Echeverria, Monsif Bouaboula. Identification of SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that has strong anti-tumor activity in wild-type and mutant ER+ breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5775.

Objective:To identify and systematically evaluate user-friendly smartphone snoring apps.Methods:The Apple iTunes app store was searched for snoring apps that allow recording and playback. Snoring apps were downloaded, evaluated and rated independently by four authors. Two patients underwent polysomnography, and the data were compared with simultaneous snoring app recordings, and one patient used the snoring app at home.Results:Of 126 snoring apps, 13 met the inclusion and exclusion criteria. The most critical app feature was the ability to graphically display the snoring events. The Quit Snoring app received the highest overall rating. When this app's recordings were compared with in-laboratory polysomnography data, app snoring sensitivities ranged from 64 to 96 per cent, and snoring positive predictive values ranged from 93 to 96 per cent. A chronic snorer used the app nightly for one month and tracked medical interventions. Snoring decreased from 200 to 10 snores per hour, and bed partner snoring complaint scores decreased from 9 to 2 (on a 0–10 scale).Conclusion:Select smartphone apps are user-friendly for recording and playing back snoring sounds. Preliminary comparison of more than 1500 individual snores demonstrates the potential clinical utility of such apps; however, further validation testing is recommended.