Reprogramming human B cells with custom heavy-chain antibodies.

The immunoglobulin locus of B cells can be reprogrammed by genome editing to produce custom or non-natural antibodies that are not induced by immunization. However, current strategies for antibody reprogramming require complex expression cassettes and do not allow for customization of the constant region of the antibody. Here we show that human B cells can be edited at the immunoglobulin heavy-chain locus to express heavy-chain-only antibodies that support alterations to both the fragment crystallizable domain and the antigen-binding domain, which can be based on both antibody and non-antibody components. Using the envelope protein (Env) from the human immunodeficiency virus as a model antigen, we show that B cells edited to express heavy-chain antibodies to Env support the regulated expression of B cell receptors and antibodies through alternative splicing and that the cells respond to the Env antigen in a tonsil organoid model of immunization. This strategy allows for the reprogramming of human B cells to retain the potential for in vivo amplification while producing molecules with flexibility of composition beyond that of standard antibodies.

Palate Shape, Drug-Induced Sleep Endoscopy Findings, and Obstructive Sleep Apnea Pharyngeal Surgery Outcomes.

OBJECTIVE: Pharyngeal surgery is a treatment option for patients with obstructive sleep apnea (OSA) unable to tolerate positive pressure therapy. This study aims to determine the association between palate shape as described by Woodson and pharyngeal surgical outcomes. STUDY DESIGN: Exploratory analysis of retrospective cohort. SETTING: Multicenter. METHODS: Three blinded reviewers assessed palate shape using drug-induced sleep endoscopy (DISE) videos from a previously-assembled cohort of adults undergoing pharyngeal surgery. Palate shape scores were examined for association with surgical outcomes with univariate and multivariate analyses. Multivariate analyses included adjustment for consensus DISE findings determined previously. RESULTS: Two hundred nine study subjects were included from 13 centers. Age was 53.7 ± 11.5 years, body mass index (BMI) was 30.3 ± 5.0 kg/m2, and 21% were female. In isolated soft palate surgery, greater GenuAP narrowing was associated with lesser odds of surgical response, whereas greater GenuLW narrowing was associated with greater odds of surgical response. These findings largely persisted after adjustment for key DISE findings, age, gender, OSA severity, BMI, and tonsil size. Other palate-shape findings were not clearly associated with surgical outcomes, although some palate-shape findings demonstrated trends toward an association with outcomes (P < .10). CONCLUSION: Greater GenuAP narrowing and GenuLW narrowing were associated with lesser and greater, respectively, odds of surgical response after isolated soft palate surgery. Palate shape and other palate shape level scores were not clearly associated with surgical outcomes. Larger studies may determine more precisely the association between palate shape and pharyngeal surgery outcomes.

Advanced Diagnostic Techniques in Obstructive Sleep Apnea.

Optimal surgical and medical management of obstructive sleep apnea requires clinically reliable identification of patterns and sites of upper airway obstruction. A wide variety of modalities have been used to evaluate upper airway obstruction. Drug-induced sleep endoscopy (DISE) and cine MRI are increasingly used to identify upper airway obstruction sites, to characterize airway obstruction patterns, to determine optimum medical and surgical treatment, and to plan individualized surgical management. Here, we provide an overview of the applications of DISE and cine MRI in assessing upper airway obstruction in children and adults with obstructive sleep apnea.

Advanced Diagnostic Techniques in Obstructive Sleep Apnea.

Optimal surgical and medical management of obstructive sleep apnea (OSA) requires clinically reliable identification of patterns and sites of upper airway obstruction. A wide variety of modalities has been used to evaluate upper airway obstruction. Drug-induced sleep endoscopy (DISE) and cine MRI are increasingly used to identify upper airway obstruction sites, to characterize airway obstruction patterns, to determine optimum medical and surgical treatment, and to plan individualized surgical management. Here, the authors provide an overview of the applications of DISE and cine MRI in assessing upper airway obstruction in children and adults with OSA.

Palate shape is associated with Unilateral Hypoglossal Nerve Stimulation Outcomes.

OBJECTIVE: The aim was to determine the potential association between palate shape and unilateral hypoglossal nerve stimulation (HNS) outcomes. METHODS: Preoperative drug-induced sleep endoscopy (DISE) videos were reviewed and scored by 3 blinded reviewers to determine airway narrowing at the hard-soft palate junction (HP), soft palate genu, and inferior velum, as described by Woodson (2014). Scoring was as follows: 1-open airway, 2-narrow, 3-severe narrowing. Overall palate shape (oblique, intermediate, or vertical) was determined based on prior criteria. Successful surgical treatment was defined by the HNS titration polysomnogram as a reduction of ≥50% in the apnea-hypopnea index (AHI) to <15 events/h. RESULTS: Of 332 adults, the majority was male (77%) with an average BMI of 29.2 ± 3.6 kg/m2 . Overall success rate was 73%. Success rate was lower in patients with vertical palate shape compared with the other shapes (56% vs. 75%, p = 0.029). HP score 3 compared with scores 2 and 1 was associated with lower success rates (60% vs. 76%, p = 0.028), but genu and velum scores were not associated with outcomes. Patients with both HP score 3 and complete oropharyngeal lateral wall-related obstruction had notably worse outcomes (22% vs. 74%, p = 0.026). HP score 3 (OR 0.45, 95%CI 0.22-0.92) and vertical palate shape (OR 0.33, 95%CI 0.15-0.78) were independently associated with lower odds of surgical response after adjustment for DISE findings, age, gender, and BMI. CONCLUSION: Vertical palate shape and narrowing at the hard-soft palate junction are independently associated with lower HNS surgical success rates. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:981-986, 2024.

Reprogramming human B cells with custom heavy chain antibodies.

We describe a genome editing strategy to reprogram the immunoglobulin heavy chain (IgH) locus of human B cells to express custom molecules that respond to immunization. These heavy chain antibodies (HCAbs) comprise a custom antigen-recognition domain linked to an Fc domain derived from the IgH locus and can be differentially spliced to express either B cell receptor (BCR) or secreted antibody isoforms. The HCAb editing platform is highly flexible, supporting antigen-binding domains based on both antibody and non-antibody components, and also allowing alterations in the Fc domain. Using HIV Env protein as a model antigen, we show that B cells edited to express anti-Env HCAbs support the regulated expression of both BCRs and antibodies, and respond to Env antigen in a tonsil organoid model of immunization. In this way, human B cells can be reprogrammed to produce customized therapeutic molecules with the potential for in vivo amplification.

Reprogramming human B cells with custom heavy chain antibodies.

We describe a genome editing strategy to reprogram the immunoglobulin heavy chain (IgH) locus of human B cells to express custom molecules that respond to immunization. These heavy chain antibodies (HCAbs) comprise a custom antigen-recognition domain linked to an Fc domain derived from the IgH locus and can be differentially spliced to express either B cell receptor (BCR) or secreted antibody isoforms. The HCAb editing platform is highly flexible, supporting antigen-binding domains based on both antibody and non-antibody components, and also allowing alterations in the Fc domain. Using HIV Env protein as a model antigen, we show that B cells edited to express anti-Env HCAbs support the regulated expression of both BCRs and antibodies, and respond to Env antigen in a tonsil organoid model of immunization. In this way, human B cells can be reprogrammed to produce customized therapeutic molecules with the potential for in vivo amplification.

Developing a Social Media Ontology Across Otolaryngology and its Subspecialties.

OBJECTIVE: To determine how social media is used in the dissemination of new information within otolaryngology, and to emphasize the importance of standardizing Twitter hashtag use. METHODS: Based on the 2019 SCImago journal rankings, the Twitter posts from the accounts of the top three journals covering each otolaryngology subspecialty were reviewed from August 1, 2020 to May 1, 2021. Twitter posts from the primary otolaryngology-related academic societies were also reviewed during this timeframe. A list of hashtags was generated based on a combination of the most common otolaryngologic procedures and most commonly used hashtags in the social media space. This list was then crowd-sourced with 10 fellowship-trained otolaryngologists for each subspecialty. RESULTS: Hashtag use among key stakeholders in the otolaryngology social media space varies considerably. For instance, #HNSCC, #HeadAndNeckSquamousCellCarcinoma, #HeadAndNeckCancer, #HeadAndNeckCancers, #OropharyngealCancer, #OropharynxCancer, #OralCancer, and #OPSCC were all commonly used hashtags to identify posts discussing oropharyngeal squamous cell carcinoma. #HeadAndNeckCancer and #HNSCC were most popular and used in a total of 85 and 65 tweets, respectively. #HeadAndNeckCancer was found alone in 32 out of 85 tweets (38%), whereas #HNSCC was found alone in 27 out of 65 tweets (42%). A standardized hashtag ontology covering all subspecialties within otolaryngology is proposed herein. CONCLUSIONS: Adoption of a standardized social media ontology within otolaryngology will improve information dissemination across all key stakeholders. Laryngoscope, 133:1595-1599, 2023.

Altered regional cerebral blood flow in obstructive sleep apnea is associated with sleep fragmentation and oxygen desaturation.

Altered cerebral perfusion has been reported in obstructive sleep apnea (OSA). Using dynamic susceptibility contrast MRI, we compared cerebral perfusion between male OSA patients and male healthy reference subjects and assessed correlations of perfusion abnormalities of OSA patients with sleep parameters and neuropsychological deficits at 3 T MRI, polysomnography and neuropsychological tests in 68 patients with OSA and 21 reference subjects. We found lower global and regional cerebral blood flow and cerebral blood volume, localized mainly in bilateral parietal and prefrontal cortices, as well as multiple focal cortical and deep structures related to the default mode network and attention network. In the correlation analysis between regional hypoperfusion and parameters of polysomnography, different patterns of regional hypoperfusion were distinctively associated with parameters of intermittent hypoxia and sleep fragmentation, which involved mainly parietal and orbitofrontal cortices, respectively. There was no association between brain perfusion and cognition in OSA patients in areas where significant association was observed in reference subjects, largely overlapping with nodes of the default mode network and attention network. Our results suggest that impaired cerebral perfusion in important areas of functional networks could be an important pathomechanism of neurocognitive deficits in OSA.

Drug-Induced Sleep Endoscopy and Hypoglossal Nerve Stimulation Outcomes: A Multicenter Cohort Study.

OBJECTIVES/HYPOTHESIS: To determine the association between findings of blinded reviews of preoperative drug-induced sleep endoscopy (DISE) and outcomes of hypoglossal nerve stimulation (HNS) for obstructive sleep apnea (OSA). STUDY DESIGN: Cohort study. METHODS: A retrospective, multicenter cohort study of 343 adults who underwent treatment of OSA with HNS from 10 academic medical centers was performed. Preoperative DISE videos were scored by four blinded reviewers using the VOTE Classification and evaluation of a possible primary structure contributing to airway obstruction. Consensus DISE findings were examined for an association with surgical outcomes based on therapy titration polysomnogram (tPSG). Treatment response was defined by a decrease of ≥50% in the apnea-hypopnea index (AHI) to <15 events/hour. RESULTS: Study participants (76% male, 60.4 ± 11.0 years old) had a body mass index of 29.2 ± 3.6 kg/m2 . AHI decreased (35.6 ± 15.2 to 11.0 ± 14.1 events/hour; P < .001) on the tPSG, with a 72.6% response rate. Complete palate obstruction (vs. none) was associated with the greatest difference in AHI improvement (-26.8 ± 14.9 vs. -19.2 ± 12.8, P = .02). Complete (vs. partial/none) tongue-related obstruction was associated with increased odds of treatment response (78% vs. 68%, P = .043). Complete (vs. partial/none) oropharyngeal lateral wall-related obstruction was associated with lower odds of surgical response (58% vs. 74%, P = .042). CONCLUSIONS: The DISE finding of primary tongue contribution to airway obstruction was associated with better outcomes, whereas the opposite was true for the oropharyngeal lateral walls. This study suggests that the role for DISE in counseling candidates for HNS extends beyond solely for excluding complete concentric collapse related to the velum. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:1676-1682, 2021.

Comparison of Traditional Upper Airway Surgery and Upper Airway Stimulation for Obstructive Sleep Apnea.

OBJECTIVE: To compare patients with moderate-severe obstructive sleep apnea (OSA) undergoing traditional single and multilevel sleep surgery to those undergoing upper airway stimulation (UAS). STUDY DESIGN: Case control study comparing retrospective cohort of patients undergoing traditional sleep surgery to patients undergoing UAS enrolled in the ADHERE registry. SETTING: 8 multinational academic medical centers. SUBJECTS AND METHODS: 233 patients undergoing prior single or multilevel traditional sleep surgery and meeting study inclusion criteria were compared to 465 patients from the ADHERE registry who underwent UAS. We compared preoperative and postoperative demographic, quality of life, and polysomnographic data. We also evaluated treatment response rates. RESULTS: The pre and postoperative apnea hypopnea index (AHI) was 33.5 and 15 in the traditional sleep surgery group and 32 and 10 in the UAS group. The postoperative AHI in the UAS group was significantly lower. The pre and postoperative Epworth sleepiness scores (ESS) were 12 and 6 in both the traditional sleep surgery and UAS groups. Subgroup analysis evaluated those patients undergoing single level palate and multilevel palate and tongue base traditional sleep surgeries. The UAS group had a significantly lower postoperive AHI than both traditional sleep surgery subgroups. The UAS group had a higher percentage of patients reaching surgical success, defined as a postoperative AHI <20 with a 50% reduction from preoperative severity. CONCLUSION: UAS offers significantly better control of AHI severity than traditional sleep surgery. Quality life improvements were similar between groups.

Methodological Quality of Systematic Reviews and Meta-analyses Published in High-Impact Otolaryngology Journals.

OBJECTIVE: To assess the methodological quality of intervention-focused systematic reviews (SRs) and meta-analyses (MAs) published in high-impact otolaryngology journals. DATA SOURCES: Ovid Medline, Embase, and Cochrane Library. REVIEW METHODS: A comprehensive search was performed for SR and MA citations from 2012 to 2017 in the 10 highest impact factor otolaryngology journals. Abstracts were screened to identify published manuscripts in which the authors indicated clearly that they were performing an SR or MA. Applying a modified typology of reviews, 4 reviewers characterized the review type as SR, MA, or another review type. A simplified version of the AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews 2) tool was used to assess the reporting and methodological quality of the SRs and MAs that were focused on interventions. RESULTS: Search and abstract screening generated 499 manuscripts that identified themselves as performing an SR or MA. A substantial number (85/499, 17%) were review types other than SRs or MAs, including 34 (7%) that were literature reviews. In total, 236 SRs and MAs focused on interventions. Over 50% of these SRs and MAs had weaknesses in at least 3 of the 16 items in the AMSTAR 2, and over 40% had weaknesses in at least 2 of the 7 critical domains. Ninety-nine percent of SRs and MAs provided critically low confidence in the results of the reviews. CONCLUSION: Intervention-focused SRs and MAs published in high-impact otolaryngology journals have important methodological limitations that diminish confidence in the results of these reviews.

Safety and efficacy of sphenopalatine ganglion stimulation for chronic cluster headache: a double-blind, randomised controlled trial.

BACKGROUND: Chronic cluster headache is the most disabling form of cluster headache. The mainstay of treatment is attack prevention, but the available management options have little efficacy and are associated with substantial side-effects. In this study, we aimed to assess the safety and efficacy of sphenopalatine ganglion stimulation for treatment of chronic cluster headache. METHODS: We did a randomised, sham-controlled, parallel group, double-blind, safety and efficacy study at 21 headache centres in the USA. We recruited patients aged 22 years or older with chronic cluster headache, who reported a minimum of four cluster headache attacks per week that were unsuccessfully controlled by preventive treatments. Participants were randomly assigned (1:1) via an online adaptive randomisation procedure to either stimulation of the sphenopalatine ganglion or a sham control that delivered a cutaneous electrical stimulation. Patients and the clinical evaluator and surgeon were masked to group assignment. The primary efficacy endpoint, which was analysed with weighted generalised estimated equation logistic regression models, was the difference between groups in the proportion of stimulation-treated ipsilateral cluster attacks for which relief from pain was achieved 15 min after the start of stimulation without the use of acute drugs before that timepoint. Efficacy analyses were done in all patients who were implanted with a device and provided data for at least one treated attack during the 4-week experimental phase. Safety was assessed in all patients undergoing an implantation procedure up to the end of the open-label phase of the study, which followed the experimental phase. This trial is registered with ClinicalTrials.gov, number NCT02168764. FINDINGS: Between July 9, 2014, and Feb 14, 2017, 93 patients were enrolled and randomly assigned, 45 to the sphenopalatine ganglion stimulation group and 48 to the control group. 36 patients in the sphenopalatine ganglion stimulation group and 40 in the control group had at least one attack during the experimental phase and were included in efficacy analyses. The proportion of attacks for which pain relief was experienced at 15 min was 62·46% (95% CI 49·15-74·12) in the sphenopalatine ganglion stimulation group versus 38·87% (28·60-50·25) in the control group (odds ratio 2·62 [95% CI 1·28-5·34]; p=0·008). Nine serious adverse events were reported by the end of the open-label phase. Three of these serious adverse events were related to the implantation procedure (aspiration during intubation, nausea and vomiting, and venous injury or compromise). A fourth serious adverse event was an infection that was attributed to both the stimulation device and the implantation procedure. The other five serious adverse events were unrelated. There were no unanticipated serious adverse events. INTERPRETATION: Sphenopalatine ganglion stimulation seems efficacious and is well tolerated, and potentially offers an alternative approach to the treatment of chronic cluster headache. Further research is need to clarify its place in clinical practice. FUNDING: Autonomic Technologies.

Previous Surgery and Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea.

OBJECTIVE: To examine whether previous palate or hypopharyngeal surgery was associated with efficacy of treatment of obstructive sleep apnea with hypoglossal nerve stimulation. STUDY DESIGN: Cohort (retrospective and prospective). SETTING: Eleven academic medical centers. SUBJECTS AND METHODS: Adults treated with hypoglossal nerve stimulation were enrolled in the ADHERE Registry. Outcomes were defined by the apnea-hypopnea index (AHI), in 3 ways: change in the AHI and 2 definitions of therapy response requiring ≥50% reduction in the AHI to a level <20 events/h (Response20) or 15 events/h (Response15). Previous palate and hypopharyngeal (tongue, epiglottis, or maxillofacial) procedures were documented. Linear and logistic regression examined the association between previous palate or hypopharyngeal surgery and outcomes, with adjustment for age, sex, and body mass index. RESULTS: The majority (73%, 217 of 299) had no previous palate or hypopharyngeal surgery, while 25% and 9% had previous palate or hypopharyngeal surgery, respectively, including 6% with previous palate and hypopharyngeal surgery. Baseline AHI (36.0 ± 15.6 events/h) decreased to 12.0 ± 13.3 at therapy titration (P < .001) and 11.4 ± 12.6 at final follow-up (P < .001). Any previous surgery, previous palate surgery, and previous hypopharyngeal surgery were not clearly associated with treatment response; for example, any previous surgery was associated with a 0.69 (95% CI: 0.37, 1.27) odds of response (Response20 measure) at therapy titration and a 0.55 (95% CI: 0.22, 1.34) odds of response (Response20 measure) at final follow-up. CONCLUSION: Previous upper airway surgery was not clearly associated with efficacy of hypoglossal nerve stimulation.

Perioperative Care of Patients With Obstructive Sleep Apnea Undergoing Upper Airway Surgery: A Review and Consensus Recommendations.

IMPORTANCE: To date, no consensus exists regarding optimal perioperative care of patients with obstructive sleep apnea (OSA) undergoing upper airway (UA) surgery. These patients are at risk related to anesthesia and postoperative analgesia, among other risks associated with difficult airway control, and may require intensified perioperative management. OBJECTIVE: To provide a consensus-based guideline by reviewing available literature and collecting expert opinion during an international consensus meeting with experts from relevant speciliaties. EVIDENCE REVIEW: In a consensus meeting conducted on April 4, 2018, a total of 47 questions covering preoperative, intraoperative, and postoperative care were formulated by 12 international experts with extensive clinical experience in the field of UA surgery for OSA. Systematic literature searches were performed by an independent information specialist and 6 researchers according to the Oxford and GRADE systems, and 164 articles published on or before December 31, 2011, were included in the analysis. Two moderators chaired the meeting according to the Amsterdam Delphi Method, including iteration of literature conclusions, expert discussion, and voting rounds. Consensus was reached when there was 70% or more agreement among experts. FINDINGS: Of 47 questions, 35 led to a recommendation or statement. The remaining 12 questions provided no additional information and were excluded in the judgment of experts. Consensus was reached for 32 recommendations. For 1 question there was less than 70% agreement among experts; therefore, consensus was not achieved. Highlights of these recommendations include (1) postoperative bleeding is a complication described for all types of UA surgery; (2) OSA is a relative risk factor for difficult mask ventilation and intubation, and plans for difficult airway management should be considered and implemented; (3) safe perioperative care should be provided, with aspects such as OSA severity, adherent use of positive airway pressure, type of surgery, and comorbidities taken into account; (4) although there is no direct evidence to date, in patients undergoing UA surgery, preoperative treatment with positive airway pressure may reduce the risk of postoperative airway complications; and (5) alternative pain management options perioperatively to reduce opioid use should be considered. CONCLUSIONS AND RELEVANCE: This consensus contains 35 recommendations and statements on the perioperative care of patients with OSA undergoing UA surgery and may be used as a guideline in daily practice.

Post-approval upper airway stimulation predictors of treatment effectiveness in the ADHERE registry.

Upper airway stimulation (UAS) has been shown to reduce severity of obstructive sleep apnoea. The aim of this study was to identify predictors of UAS therapy response in an international multicentre registry.Patients who underwent UAS implantation in the United States and Germany were enrolled in an observational registry. Data collected included patient characteristics, apnoea/hypopnoea index (AHI), Epworth sleepiness scale (ESS), objective adherence, adverse events and patient satisfaction measures. Post hoc univariate and multiple logistic regression were performed to evaluate factors associated with treatment success.Between October 2016 and January 2018, 508 participants were enrolled from 14 centres. Median AHI was reduced from 34 to 7 events·h-1, median ESS reduced from 12 to 7 from baseline to final visit at 12-month post-implant. In post hoc analyses, for each 1-year increase in age, there was a 4% increase in odds of treatment success. For each 1-unit increase in body mass index (BMI), there was 9% reduced odds of treatment success. In the multivariable model, age persisted in serving as statistically significant predictor of treatment success.In a large multicentre international registry, UAS is an effective treatment option with high patient satisfaction and low adverse events. Increasing age and reduced BMI are predictors of treatment response.