Early Voice and Swallowing Disturbance Incidence and Risk Factors After Revision Anterior Cervical Discectomy and Fusion Using a Multidisciplinary Surgical Approach: A Retrospective Cohort Evaluation of a Prospective Database.

BACKGROUND AND OBJECTIVES: Dysphagia and vocal cord palsy (VCP) are common otolaryngological complications after revision anterior cervical discectomy and fusion (rACDF) procedures. Our objective was to determine the early incidence and risk factors of VCP and dysphagia after rACDF using a 2-team approach. METHODS: Single-institution, retrospective analysis of a prospectively collected database of patients undergoing rACDF was enrolled from September 2010 to July 2021. Of 222 patients enrolled, 109 patients were included in the final analysis. All patients had prior ACDF surgery with planned revision using a single otolaryngologist and single neurosurgeon. MD Anderson Dysphagia Inventory and fiberoptic endoscopic evaluation of swallowing (FEES) were used to assess dysphagia. VCP was assessed using videolaryngostroboscopy. RESULTS: Seven patients (6.7%) developed new postoperative VCP after rACDF. Most cases of VCP resolved by 3 months postoperatively (mean time-to-resolution 79 ± 17.6 days). One patient maintained a permanent deficit. Forty-one patients (37.6%) reached minimum clinically important difference (MCID) in their MD Anderson Dysphagia Inventory composite scores at the 2-week follow-up (MCID decline of ≥6), indicating new clinically relevant swallowing disturbance. Forty-nine patients (45.0%) had functional FEES Performance Score decline. On univariate analysis, there was an association between new VCPs and the number of cervical levels treated at revision ( P = .020) with long-segment rACDF (≥4 levels) being an independent risk factor ( P = .010). On linear regression, there was an association between the number of levels treated previously and at revision for FEES Performance Score decline ( P = .045 and P = .002, respectively). However, on univariate analysis, sex, age, body mass index, operative time, alcohol use, smoking, and individual levels revised were not risk factors for reaching FEES Performance Score decline nor MCID at 2 weeks postoperatively. CONCLUSION: VCP is more likely to occur in long-segment rACDF but is often temporary. Clinically relevant and functional rates of dysphagia approach 37% and 45%, respectively, at 2 weeks postoperatively after rACDF.

Inappropriate image duplications in rhinology research publications.

KEY POINTS: Duplicated images in research articles erode integrity and credibility of biomedical science. Forensic software is necessary to detect figures with inappropriately duplicated images. This analysis reveals a significant issue of inappropriate image duplication in our field.

Hypoxia-induced cystic fibrosis transmembrane conductance regulator dysfunction is a universal mechanism underlying reduced mucociliary transport in sinusitis.

INTRODUCTION: Hypoxia due to sinus obstruction is a major pathogenic mechanism leading to sinusitis. The objective of the current study is to define the electrophysiologic characteristics of hypoxia in vitro and in vivo. METHODS: Cystic fibrosis bronchoepithelial cells expressing wild-type cystic fibrosis transmembrane conductance regulator (CFTR) and human sinonasal epithelial cells were exposed to 1% or atmospheric O2 for 24 h. Time-dependent production of cytoplasmic free radicals was measured. Cells were subjected to Ussing chamber and patch clamp technique where CFTR currents were recorded in whole-cell and cell-attached mode for single channel studies. Indices of mucociliary transport (MCT) were measured using micro-optical coherence tomography. In a rabbit hypoxic maxillary sinus model, tissue oxygenation, relative mRNA expression of HIF-1α, pH, sinus potential difference (SPD), and MCT were determined. RESULTS: Ussing chamber (p < 0.05), whole-cell (p < 0.001), and single channel patch-clamp (p < 0.0001) showed significant inhibition of Cl- currents in hypoxic cells. Cytoplasmic free radicals showed time-dependent elevation peaking at 4 h (p < 0.0001). Airway surface liquid (p < 0.0001), periciliary liquid (p < 0.001), and MCT (p < 0.01) were diminished. Co-incubation with the free radical scavenger glutathione negated the impact of hypoxia on single channel currents and MCT markers. In sinusitis rabbits, mucosa exhibited low tissue oxygenation (p < 0.0001), increased HIF1α mRNA (p < 0.05), reduced pH (p < 0.01), and decreased MCT (p < 0.001). SPD measurements demonstrated markedly diminished transepithelial Cl- transport (p < 0.0001). CONCLUSION: Hypoxia induces severe CFTR dysfunction via free radical production causing reduced MCT in vitro and in vivo. Improved oxygenation is critical to reducing the impact of persistent mucociliary dysfunction.

Glutathione and bicarbonate nanoparticles improve mucociliary transport in cystic fibrosis epithelia.

INTRODUCTION: Cystic fibrosis (CF) airway disease is characterized by thick mucus and impaired mucociliary transport (MCT). Loss of functional cystic fibrosis transmembrane receptor (CFTR) leads to acidification and oxidation of airway surface mucus. Replacing bicarbonate (HCO3 - ) topically fails due to rapid reabsorption and neutralization, while the scavenging antioxidant, glutathione sulfhydryl (GSH), is also rapidly degraded. The objective of this study is to investigate GSH/NaHCO3 nanoparticles as novel strategy for CF airway disease. METHODS: GSH/NaHCO3 poly (lactic-co-glycolic acid) nanoparticles were tested on primary CF (F508del/F508del) epithelial cultures to evaluate dose-release curves, surface pH, toxicity, and MCT indices using micro-optical coherence tomography. In vivo tests were performed in three rabbits to assess safety and toxicity. After 1 week of daily injections, histopathology, computed tomography (CT), and blood chemistries were performed and compared to three controls. Fluorescent nanoparticles were injected into a rabbit with maxillary sinusitis and explants visualized with confocal microscopy. RESULTS: Sustained release of GSH and HCO3 - with no cellular toxicity was observed over 2 weeks. Apical surface pH gradually increased from 6.54 ± 0.13 (baseline) to 7.07 ± 0.10 (24 h) (p < 0.001) and 6.87 ± 0.05 at 14 days (p < 0.001). MCT, ciliary beat frequency, and periciliary liquid were significantly increased. When injected into the maxillary sinuses of rabbits, there were no changes to histology, CT, or blood chemistries. Nanoparticles penetrated rabbit sinusitis mucus on confocal microscopy. CONCLUSION: Findings suggest that GSH/NaHCO3 - nanoparticles are a promising treatment option for viscous mucus in CF and other respiratory diseases of mucus obstruction such as chronic rhinosinusitis.

Effect of Perioperative Antithrombotics on Postoperative Transfusion and Hematoma in Head and Neck Free Flaps.

Objective: To explore if antiplatelet or anticoagulant therapy increases the risk of transfusion requirement or postoperative hematoma formation in patients undergoing microvascular reconstruction for head and neck defects. Study Design: Retrospective cohort study. Setting: Departments of Otolaryngology-Head and Neck Surgery at the University of Alabama at Birmingham, the University of Colorado, and the University of California Irvine. Methods: A multi-institutional, retrospective review on microvascular reconstruction of the head and neck between August 2013 to July 2021. Perioperative antithrombotic data were collected to examine predictors of postoperative transfusion and hematoma. Results: A total of 843 free flaps were performed. Preoperative hemoglobin, hematocrit, operative time, and flap type were positive predictors of postoperative transfusion in both bivariate (P < .0001) and multivariate analyses (P < .0001). However, neither anticoagulation nor antiplatelet therapy were predictive of postoperative transfusion rates and hematoma formation. Conclusion: Antithrombotic regimens do not increase the risk of postoperative transfusion or hematoma in head and neck microvascular reconstruction. Based on this limited data, perioperative antithrombotic regimens can be considered in patients who may otherwise be at risk for these postoperative complications.

A Survey of Otolaryngology Residency Programs on Adapting to the United States Medical Licensing Examination (USMLE) Step 1 Transitioning to Pass/Fail.

Objectives In February 2020, the National Board of Medical Examiners (NBME) announced that the United States Medical Licensing Examination (USMLE) Step 1 licensing examination would change from a numerical score to Pass/Fail (P/F). After implementation, many believe that USMLE-Step 2-Clinical Knowledge (CK) will become an important metric for students applying to otolaryngology (ENT). The purpose of this study is to determine factors important to resident selection after these changes. Methods A survey containing 15 questions related to resident selection practices and how changing USMLE Step 1 to P/F would impact future resident selection was designed. It was distributed to all ENT residency programs accredited by the Accreditation Council for Graduate Medical Education (ACGME). Results Forty percent of programs responded; 66% (95% confidence interval (CI): 51.1%-78.4%) felt that changing Step 1 scoring would not lead to students being more prepared for clinical rotations; 55% believe class rank will increase in significance (95% CI: 35.7%-64.3%). There was also an increase in the importance of Step 2 CK, which had a mean ranking of 10.67 prior to changes in Step 1 scoring and increased to 7.80 after P/F. Conclusions The changes in Step 1 scoring will likely lead to increasing importance of other objective measures like class rank or Step 2 CK. This may defeat the intended purpose put forth by the NBME. Therefore, further guidance on measures correlated with student performance as a resident will be integral to the selection process.

Red ginseng aqueous extract improves mucociliary transport dysfunction and histopathology in CF rat airways.

BACKGROUND: We previously discovered that Korean red ginseng aqueous extract (RGAE) potentiates the TMEM16A channel, improved mucociliary transport (MCT) parameters in CF nasal epithelia in vitro, and thus could serve as a therapeutic strategy to rescue the MCT defect in cystic fibrosis (CF) airways. The hypothesis of this study is that RGAE can improve epithelial Cl- secretion, MCT, and histopathology in an in-vivo CF rat model. METHODS: Seventeen 4-month old CFTR-/- rats were randomly assigned to receive daily oral control (saline, n = 9) or RGAE (Ginsenosides 0.4mg/kg/daily, n = 8) for 4 weeks. Outcomes included nasal Cl- secretion measured with the nasal potential difference (NPD), functional microanatomy of the trachea using micro-optical coherence tomography, histopathology, and immunohistochemical staining for TMEM16a. RESULTS: RGAE-treated CF rats had greater mean NPD polarization with UTP (control = -5.48 +/- 2.87 mV, RGAE = -9.49 +/- 2.99 mV, p < 0.05), indicating, at least in part, potentiation of UTP-mediated Cl- secretion through TMEM16A. All measured tracheal MCT parameters (airway surface liquid, periciliary liquid, ciliary beat frequency, MCT) were significantly increased in RGAE-treated CF rats with MCT exhibiting a 3-fold increase (control, 0.45+/-0.31 vs. RGAE, 1.45+/-0.66 mm/min, p < 0.01). Maxillary mucosa histopathology was markedly improved in RGAE-treated cohort (reduced intracellular mucus, goblet cells with no distention, and shorter epithelial height). TMEM16A expression was similar between groups. CONCLUSION: RGAE improves TMEM16A-mediated transepithelial Cl- secretion, functional microanatomy, and histopathology in CF rats. Therapeutic strategies utilizing TMEM16A potentiators to treat CF airway disease are appropriate and provide a new avenue for mutation-independent therapies.

The Modified Medial Maxillectomy as a Radical or Extended,-yet Still Functional,-Technique in Sinus Surgery.

BACKGROUND: Endoscopic sinus surgery with a middle meatal antrostomy is a common intervention in the treatment algorithm for maxillary sinus pathologies. However, this procedure has its origins in a time when simple ventilation of the sinus cavity was the primary (and only often) goal of surgery. In some patients, persistent mucociliary dysfunction occurs despite ventilatory surgery. Although the endoscopic modified medial maxillectomy (MMM) was originally described for tumour surgery, it provides a radical yet still functional option to overcome chronic sinus dysfunction. OBJECTIVE: The goal of this study was to describe the functional status of a post-MMM sinus cavity. METHODS: A consecutive series of patients who underwent at least a unilateral MMM by three tertiary rhinologists were retrospectively reviewed. Prospectively collected data included patient demographics (including age, gender, smoking status and comorbidities), disease-specific factors, microbiology, and preoperative patient-reported symptoms based on the 22-item Sinonasal Outcome Test-22 (SNOT-22) and radiology. The primary outcome of the study was the presence of sinus dysfunction, defined by mucostasis or pooling on endoscopic examination at the last follow-up. Secondary outcomes included the need for revision surgery as a result of sinus dysfunction and the improvement in SNOT-22 score. RESULTS: A total of 551 medial maxillectomies (47.0% female, 52.9 ± 16.8 years) were performed. Very few patients experienced post-operative sustained mucostasis following MMM (10.2%) and even fewer required revision surgery (5.0%). Chronic obstructive pulmonary disease (odds ratio (OR) = 6.82, P < 0.002.) and asthma (OR = 2.48, P = 0.03) were associated with mucostasis. Patients who underwent an MMM experienced a notable postoperative improvement in SNOT-22 score (45.9 ± 23.7 (pre-op) vs. 23.6 ± 19.4 (post-op); paired t-test, P < 0.0001). CONCLUSION: The MMM, whether performed for access to pathology or with the intent to avoid mucous 'sumping' with the sinus, can provide a long-term functional maxillary sinus cavity with minimal morbidity.

Effect of Perioperative Antithrombotics on Head and Neck Microvascular Free Flap Survival After Anastomotic Revision.

OBJECTIVE: To determine if antithrombotic therapy improves head and neck microvascular free flap survival following anastomotic revision. STUDY DESIGN: A retrospective review of all patients with microvascular free tissue transfer to the head and neck between August 2013 and July 2021. SETTING: Otolaryngology-Head and Neck Surgery Departments at University of Alabama at Birmingham, University of Colorado, and University of California Irvine. METHODS: Perioperative use of anticoagulation, antiplatelets, intraoperative heparin bolus, tissue plasminogen activator (tPA) and vasopressor use, and leech therapy were collected plus microvascular free flap outcomes. The primary endpoint was free flap failure. Analyses of free flaps that underwent anastomotic revision with or without thrombectomy were performed. RESULTS: A total of 843 microvascular free flaps were included. The overall rate of flap failure was 4.0% (n = 34). The overall rate of pedicle anastomosis revision (artery, vein, or both) was 5.0% (n = 42) with a failure rate of 47.6% (n = 20) after revision. Anastomotic revision significantly increased the risk of flap failure (odds ratio [OR] 52.68, 95% confidence interval [CI] [23.90, 121.1], p < .0001) especially when both the artery and vein were revised (OR 9.425, 95% CI [2.117, 52.33], p = .005). Free flap failure after the anastomotic revision was not affected by postoperative antiplatelet therapy, postoperative prophylactic anticoagulation, intraoperative heparin bolus, tPA, and therapeutic anticoagulation regardless of which vessels were revised and if a thrombus was identified. CONCLUSION: In cases of microvascular free tissue transfer pedicle anastomotic revision, the use of antithrombotic therapy does not appear to significantly change free flap survival outcomes.

Advances in Sinus Surgery for Nasal Polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is comprised of a diverse group of endotypes that cause significant morbidity for afflicted patients. While endoscopic sinus surgery helps ameliorate the disease, polyps frequently recur. Newer strategies are intended to provide access for topical steroid irrigations in attempts to improve the disease process and quality of life, and decrease overall recurrence of polyps. OBJECTIVE: To review the current literature examining the latest surgical approaches for CRSwNP. METHODS: Review article. RESULTS: In dealing with the recalcitrant nature of CRSwNP, surgical techniques have simultaneously become more nuanced and aggressive. Bony resection in anatomically unfavorable areas such as the frontal, maxillary, and sphenoid outflow regions, replacing diseased or denuded mucosa with healthy grafts or flaps at the neo-ostia, and introducing drug-eluting biomaterials to newly opened sinus outflow tracts are highlights in the recent advancements in sinus surgery for CRSwNP. The Draf 3 or modified endoscopic Lothrop procedure has become a standard technique and demonstrated to improve quality of life and decrease polyp recurrence. A number of mucosal grafting or mucosal flap techniques have been described that cover exposed bone of the neo-ostium and evidence shows that this improves healing and diameter of the Draf 3. Partial middle turbinectomy, while controversial, appears to help decrease polyp recurrence in long-term follow-up studies. Modified endoscopic medial maxillectomy improves access to the maxillary sinus mucosa, facilitates debridement and, particularly, in the cystic fibrosis nasal polyp patient, improves overall management of the disease. Sphenoid drill-out procedure provides wider access for topical steroid irrigations and also may improve management of CRSwNP. CONCLUSION: Surgical intervention remains a mainstay of therapy for CRSwNP. Newer techniques revolve around improving access for topical steroid therapy.

Long-duration pain block for postoperative anesthesia after endoscopic sinus surgery.

KEY POINTS: A long-duration pain block did not decrease postoperative pain or opioid consumption. Extended sinus procedures do not lead to additional postoperative pain or opioid consumption.

#ENT: Otolaryngology Residency Programs Create Social Media Platforms to Connect With Applicants During COVID-19 Pandemic.

OBJECTIVE: To determine which otolaryngology residency programs have social media platforms and to review which programs are utilizing platforms to advertise virtual open houses and virtual subinternships for residency applicants. STUDY DESIGN: Cross-sectional study. SETTING: The study was conducted online by reviewing all accredited otolaryngology residency programs in the United States participating in the Electronic Residency Application Service. METHODS: Otolaryngology residency programs were reviewed for social media presence on Instagram, Twitter, and Facebook. Social media posts were evaluated for virtual open houses and virtual subinternships. Residency websites and the Visiting Student Application Service were evaluated for the presence of virtual subinternships. All data were collected between September 5, 2020, and September 9, 2020. This study did not require approval from the University of Alabama at Birmingham Institutional Review Board for Human Use. RESULTS: Among 118 otolaryngology residency programs, 74 (62.7%) participate on Instagram, 52 (44.1%) participate on Twitter, and 44 (37.3%) participate on Facebook. Fifty-one Instagram accounts, 20 Twitter accounts, and 4 Facebook accounts have been created during 2020. Forty-two (36%), 30 (25.4%), and 15 (13%) programs are promoting virtual open houses on Instagram, Twitter, and Facebook, respectively. Two programs on the Visiting Student Application Service offered virtual subinternships. Seven residency program websites offered virtual subinternships. Nine, 6, and 1 program offered virtual subinternships on Instagram, Twitter, and Facebook, respectively. CONCLUSION: This study demonstrates that social media presence on Instagram and Twitter among otolaryngology residency programs has substantially grown in 2020 at a higher rate compared to previous years. These data suggest that otolaryngology residency programs are finding new ways to reach out to applicants amid an unprecedented type of application cycle due to the challenges presented by COVID-19. Many programs are advertising virtual open houses via social media platforms to connect with applicants, and a few programs are offering virtual subinternships to replace traditional subinternships.

Individual SNOT-22 Items Aid in Differentiating Between Spontaneous Cerebrospinal Fluid Rhinorrhea and Chronic Rhinosinusitis Without Nasal Polyps.

OBJECTIVES: Spontaneous cerebrospinal fluid (CSF) rhinorrhea is a diagnostic challenge due to its overlapping symptomatology with other sinonasal diseases. The objective of this study was to investigate whether items on the sinonasal outcome test (SNOT)-22 could suggest a diagnosis of spontaneous CSF rhinorrhea versus chronic rhinosinusitis without nasal polyps (CRSsNP). METHODS: A multi-institutional retrospective chart review of patients with spontaneous CSF rhinorrhea and a control group of CRSsNP patients was performed. Individual SNOT-22 scores and domain scores were compared. RESULTS: One hundred fifteen patients were included in both cohorts. Of the patients in the CSF rhinorrhea group, 48% were misdiagnosed as chronic rhinosinusitis (CRS) prior to the correct identification of a CSF leak. On bivariate analysis, the CSF rhinorrhea group scored significantly higher on the SNOT-22 for runny nose (P < .001) and was more likely to designate this symptom as most important (P < .001). The CRSsNP group scored significantly higher in nasal blockage (P < .001), thick nasal discharge (P < .001), facial pain/pressure (P < .001), and in the ear/facial (P < .001) and rhinologic (P = .003) domains. Multivariable logistic regression revealed that runny nose (P < .001) was most predictive of spontaneous CSF rhinorrhea while nasal blockage (P < .001), thick nasal discharge (P < .001), and facial pain/pressure (P = .001) were predictive of CRSsNP after adjusting for relevant confounders. No significant difference was observed in total SNOT-22 scores between groups (P = .676). CONCLUSIONS: Spontaneous CSF rhinorrhea is commonly misdiagnosed as other sinonasal pathologies. However, individual SNOT-22 items can help aid in suggesting a CSF leak. Spontaneous CSF rhinorrhea should be suspected in patients who have high SNOT-22 scores for runny nose and report this symptom as most important, but have lower scores related to the other cardinal symptoms of CRS.

Optic nerve sheath diameter correlates to intracranial pressure in spontaneous CSF leak patients.

BACKGROUND: Spontaneous cerebrospinal fluid (sCSF) leaks develop from pressure erosion due to idiopathic intracranial hypertension, treatment of which is paramount to preventing recurrence. Direct measurements of intracranial pressure (ICP) for monitoring response to treatment via lumbar drain (LD) or ventriculostomy are invasive and have risks. The objectives of this study are to determine whether ultrasonographic measurements of optic nerve sheath diameter (ONSD) correlate with LD ICP in patients with sCSF leaks undergoing treatment, and whether ONSDs are larger in patients with sCSF leaks than controls. METHODS: Subjects with sCSF leaks and controls were prospectively recruited. ONSD, sex, and body mass index (BMI) were analyzed. For sCSF leak subjects, ultrasonography was performed at the time of LD opening and each pressure check postoperatively, including the acetazolamide response. In control patients, measurements were obtained at the time of surgery. Pearson's correlation between ONSD and ICP was performed. RESULTS: Subjects with sCSF leaks (n = 9, age 52.4 ± 9.5, all female) and controls (n = 8, age 60.1 ± 14.8, two females) had significantly different BMIs, 38.4 ± 8.1 vs. 29.2 ± 4.8, t(15) = 2.793, p = 0.014. ONSD was strongly correlated with ICP measurements (r = 0.583, p = 0.002). However, percentage change in ONSD and ICP measurements were more strongly correlated (r = 0.733, p < 0.001). Patients with sCSF leaks had significantly higher ONSDs than controls, 0.63 cm ± 0.044 vs. 0.56 cm ± 0.074, t(15) = 2.329, p = 0.034. CONCLUSION: ONSD significantly correlated with ICP in sCSF leak patients and was wider in sCSF leak subjects than controls. Ultrasonography has utility in monitoring the ICP response to acetazolamide.

SNOT-22 Quality of Life Scores Improve After Endoscopic Endonasal Repair of Spontaneous Cerebrospinal Fluid Rhinorrhea.

OBJECTIVES: Patients with spontaneous cerebrospinal fluid (CSF) rhinorrhea can experience significant sinonasal symptom burden, leading to poor quality of life (QOL). The objective of this study was to investigate sinonasal outcome test-22 (SNOT-22) scores in patients undergoing endoscopic endonasal surgery for spontaneous CSF rhinorrhea and compare them to patients undergoing endoscopic sinus surgery (ESS) for chronic rhinosinusitis without nasal polyps (CRSsNP). METHODS: A multi-institutional retrospective review of patients with spontaneous CSF rhinorrhea and CRSsNP was performed. Pre-surgery and post-surgery SNOT-22 scores and domains were compared within each group. Improvements in SNOT-22 scores after surgery were compared between the groups. RESULTS: Ninety-one patients were in the CSF rhinorrhea group and 105 patients were in the CRSsNP group. Within each group, surgery significantly improved total SNOT-22 scores, domain scores, and most of the individual symptoms. Comparing the 2 groups revealed similar improvements in total SNOT-22 scores (P = .244). The CSF rhinorrhea group improved more in runny nose (P < .001), postnasal discharge (P < .001), wake up at night (P = .024), and embarrassed (P = .002). The CRSsNP group improved more in sneezing (P = .027), nasal blockage (P < .001), decreased sense of smell/taste (P = .011), thick nasal discharge (P < .001), facial pain/pressure (P = .008), and the ear/facial domain (P = .010). CONCLUSIONS: Patients with spontaneous CSF rhinorrhea experience significant symptom burden. Those who undergo CSF leak repair should experience significant improvement in QOL similar to patients who undergo ESS for CRSsNP as measured by SNOT-22.

Unified Airway-Cystic Fibrosis.

Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR channel is responsible for the transport of the anions (chloride and bicarbonate) across airway epithelia. Patients with CF have thick mucus, disrupted mucociliary transport, and chronic bacterial infections in the upper and lower airways. In this article, the pathophysiology of CFTR dysfunction and its impact on the united airway are reviewed as well as the treatment strategies for patients with chronic rhinosinusitis-related CF and acquired CFTR dysfunction.