Airway injury induces alveolar epithelial and mesenchymal responses mediated by macrophages.

Acute injury in the airways or the lung activates local progenitors and stimulates changes in cell-cell interactions to restore homeostasis, but it is not appreciated how more distant niches are impacted. We utilized mouse models of airway-specific epithelial injury to examine secondary tissue-wide alveolar, immune, and mesenchymal responses. Single-cell transcriptomics and in vivo validation revealed transient, tissue-wide proliferation of alveolar type 2 (AT2) progenitor cells after club cell-specific ablation. The AT2 cell proliferative response was reliant on alveolar macrophages (AMs) via upregulation of Spp1 which encodes the secreted factor Osteopontin. A previously uncharacterized mesenchymal population we termed Mesenchymal Airway/Adventitial Niche Cell 2 (MANC2) also exhibited dynamic changes in abundance and a pro-fibrotic transcriptional signature after club cell ablation in an AM-dependent manner. Overall, these results demonstrate that acute airway damage can trigger distal lung responses including altered cell-cell interactions that may contribute to potential vulnerabilities for further dysregulation and disease.

Lentiviral expression of wild-type LAMA3A restores cell adhesion in airway basal cells from children with epidermolysis bullosa.

The hallmark of epidermolysis bullosa (EB) is fragile attachment of epithelia due to genetic variants in cell adhesion genes. We describe 16 EB patients treated in the ear, nose, and throat department of a tertiary pediatric hospital linked to the United Kingdom's national EB unit between 1992 and 2023. Patients suffered a high degree of morbidity and mortality from laryngotracheal stenosis. Variants in laminin subunit alpha-3 (LAMA3) were found in 10/15 patients where genotype was available. LAMA3 encodes a subunit of the laminin-332 heterotrimeric extracellular matrix protein complex and is expressed by airway epithelial basal stem cells. We investigated the benefit of restoring wild-type LAMA3 expression in primary EB patient-derived basal cell cultures. EB basal cells demonstrated weak adhesion to cell culture substrates, but could otherwise be expanded similarly to non-EB basal cells. In vitro lentiviral overexpression of LAMA3A in EB basal cells enabled them to differentiate in air-liquid interface cultures, producing cilia with normal ciliary beat frequency. Moreover, transduction restored cell adhesion to levels comparable to a non-EB donor culture. These data provide proof of concept for a combined cell and gene therapy approach to treat airway disease in LAMA3-affected EB.

Epithelial stem and progenitor cells of the upper airway.

The upper airway acts as a conduit for the passage of air to the respiratory system and is implicated in several chronic diseases. Whilst the cell biology of the distal respiratory system has been described in great detail, less is known about the proximal upper airway. In this review, we describe the relevant anatomy of the upper airway and discuss the literature detailing the identification and roles of the progenitor cells of these regions.

Open and Thoracoscopic Aortopexy for Airway Malacia in Children: 15 Year Single Centre Experience.

OBJECTIVES: The objective was to report and analyse the characteristics and results of open aortopexy and thoracoscopic aortopexy for the treatment of airway malacia in a paediatric population. METHODS: We report a retrospective consecutive case series of paediatric patients undergoing aortopexy for the treatment of airway malacia at a quaternary referral centre between December 2006 and January 2021. Outcome measures included days to extubation, continued need for non-invasive ventilation, further intervention in the form of tracheostomy and death. RESULTS: 169 patients underwent aortopexy: 147 had open procedures (135 via median/limited median sternotomy and 12 thoracotomy) and 22 thoracoscopic. Mean follow up was 8.46 yrs (range 1-20 yrs). Most common site of airway malacia was the trachea (n = 106, 62.7 %), and 48 (28.4 %) had additional involvement at the bronchi with tracheobronchomalacia (TBM). 15 (8.9 %) had bronchomalacia (BM) only. Incidence of bronchial disease was lower in the thoracoscopic than open group (13.6 % vs 40.82 %; p < 0.0001). Mean time to extubation was 1.45 days, 2.59 days, 5.23 days in tracheomalacia, TBM and BM groups, respectively (p = 0.0047). Mean time to extubation was 1.35 days, 2 days, 3.67 days, and 5 days in patients with external vascular compression, TOF/OA, primary airway malacia, and laryngeal reconstruction, respectively (p = 0.0002). There were 21 deaths across the cohort, and all were in the open group. 71.4 % (n = 15) had bronchial involvement of their airway malacia. CONCLUSIONS: Open and thoracoscopic aortopexy are effective treatments for airway malacia in children. We have identified that involvement of the bronchi is a risk factor for adverse outcomes, and the optimum treatment for this patient cohort is still debatable. LEVEL OF EVIDENCE: IV. TYPE OF STUDY: Retrospective Study.

Suspension laryngoscopy experiences in a tertiary airway service: A prospective study of 150 procedures.

OBJECTIVES: In most cases, suspension laryngoscopy (SL) is efficient, bloodless and with minimal post-procedure discomfort. We aimed to identify predictive patient factors for acceptable surgical views at SL as well as quantify our tertiary airway unit's complication rates. DESIGN: Prospective cohort study of 150 consecutive microlaryngoscopy procedures involving SL over an 8-month period between November 2019 and July 2020. Patients were assessed preoperatively for pre-existing oral, temporomandibular, dental, pharyngeal or laryngeal pathology, interincisor distance and qualitative gross limitations to neck extension and forward head posture. Intraoperatively, the laryngoscopic view was graded by anaesthetic and surgical teams, and complications were recorded on patient interview in recovery. SETTING: Tertiary adult airway service for predominantly benign pathology. RESULTS: Adequate surgical views were obtained in 149/150 procedures. BMI had a weak positive correlation with a more difficult view (r = .22, p = .008) but did not correlate with a statistically significant increase in any complication. There was a weak negative correlation between age and interincisor gap (r = -.20, p = .014), and wider mouth opening correlated very weakly with a lower incidence of sore throat (r = -.19, p = .023). Gross macroglossia showed a significant moderate positive correlation with tongue symptoms (r = .45, p = 1.611 × 10-8 ). CONCLUSION: In the context of an experienced airway unit with a high caseload of predominantly benign pathology, SL is very effective and safe with low associated morbidity and no mortality. The most common complication of SL is temporary sore throat and there remain recognised risks of temporary tongue and dental symptoms.

Sarcoidosis of the ear, nose and throat: A review of the literature.

OBJECTIVES: Sarcoidosis is a multisystemic inflammatory disease with extrathoracic manifestations, most commonly affecting the young and middle-aged, female and Black populations. Diagnosis usually requires evidence of non-caseating granulomata and, when treated, prognosis is usually favourable. We aim to establish the incidence, clinical features and optimal treatment of ENT manifestations of this disease. DESIGN: We performed a PubMed literature review to determine the evidence base supporting this. RESULTS: ENT manifestations are present in 5%-15% of patients with sarcoidosis, often as a presenting feature, and require vigilance for swift recognition and coordinated additional treatment specific to the organ. Laryngeal sarcoidosis presents with difficulty in breathing, dysphonia and cough, and may be treated by speech and language therapy (SLT) or intralesional injection, dilatation or tissue reduction. Nasal disease presents with crusting, rhinitis, nasal obstruction and anosmia, usually without sinus involvement. It is treated by topical nasal or intralesional treatments but may also require endoscopic sinus surgery, laser treatment or even nasal reconstruction. Otological disease is uncommon but includes audiovestibular symptoms, both sensorineural and conductive hearing loss, and skin lesions. CONCLUSIONS: The consequences of ENT manifestations of sarcoidosis can be uncomfortable, disabling and even life-threatening. Effective management strategies require good diagnostic skills and use of specific therapies combined with established treatments such as corticosteroids. Comparisons of treatment outcomes are needed to establish best practice in this area.

A Prospective Study of Voice, Swallow, and Airway Outcomes Following Tracheostomy for COVID-19.

OBJECTIVE: The COVID-19 pandemic has led to unprecedented demands on healthcare with many requiring intubation. Tracheostomy insertion has often been delayed and the enduring effects of this on voice, swallow, and airway outcomes in COVID-19 tracheostomy patients are unknown. The aim of this study was to prospectively assess these outcomes in this patient cohort following hospital discharge. METHODS: All COVID-19 patients who had undergone tracheostomy insertion, and were subsequently decannulated, were identified at our institution and followed up 2 months post-discharge. Patient-reported (PROMS) and clinician-reported outcome measures, endoscopic examination, and spirometry were used to assess voice, swallow, and airway outcomes. RESULTS: Forty-one patients were included in the study with a mean age of 56 years and male:female ratio of 28:13. Average duration of endotracheal intubation was 24 days and 63.4% of tracheostomies were performed at day 21 to 35 of intubation. 53.7% had an abnormal GRBAS score and 30% reported abnormal swallow on EAT-10 questionnaire. 81.1% had normal endoscopic examination of the larynx, however, positive endoscopic findings correlated with the patient self-reported VHI-10 (P = .036) and EAT-10 scores (P = .027). 22.5% had spirometric evidence of fixed upper airway obstruction using the Expiratory-Disproportion Index (EDI) and Spearman correlation analysis showed a positive trend between abnormal endoscopic findings and EDI scores over 50 (P < .0001). CONCLUSION: The preliminary results of this study reveal a high incidence of laryngeal injury among patients who underwent intubation and tracheostomy insertion during the COVID-19 pandemic. As these patients continue to be followed up, the evolution of these complications will be studied. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E1918-E1925, 2021.

A pilot study to determine the effects of nasal co-phenylcaine on drug-induced sleep endoscopy.

PURPOSE: The use of nasal decongestant and nasal anaesthesia is currently not recommended during drug-induced sleep endoscopy (DISE) according to the European position paper. The evaluation of the effects of nasal decongestant/anaesthesia on DISE has not been performed before and our aim is to perform a pilot study to determine whether nasal decongestants/anaesthesia affects DISE outcomes. METHODS: 27 patients undergoing DISE for OSA or for simple snoring were included. On each patient, DISE was performed twice, before and approximately 10 min after the administration of two puffs of co-phenylcaine nasal spray (lidocaine hydrochloride 5%, phenylephrine 0.5%, and benzalkonium chloride 0.01%) into each nostril. A nasal peak inspiratory flow was used for the objective assessment of nasal airway obstruction. During the first and the second DISE the loudness of the snoring was also recorded. RESULTS: Change in DISE total grading after nasal spray administration was not statistically significant. For the same grading, changes in percentage of contribution to collapse were not statistically significant. Sex, AHI, BMI, tonsils grade, presence of rhinitis, turbinate hypertrophy, nasal septal deviation, or nasal peak inspiratory flow limitation had no influence on the effect of nasal spray. Co-phenylcaine did not significantly influence the loudness of snoring. CONCLUSIONS: Our pilot study supports the use of co-phenylcaine nasal spray during DISE and the positive effects of the nasal spray do not influence the grading outcome. Importantly, the decongestant enhances the nasal assessment during DISE and potentially aids in the diagnosis of nasal obstruction while the nasal anaesthetic component may be beneficial by reducing nasal discomfort during DISE and thereby helping to reduce the total dose of intravenous anaesthetic administered. However, further studies on a larger population are needed to confirm our results.

Pyogenic granuloma gravidarum: a case in the nasal cavity and the use of MRI as a preoperative surgical aide.

Pyogenic granuloma gravidarum is a benign fibrovascular proliferative lesion usually involving the oral gingivae in pregnant patients. While it also occurs, although less frequently, on other oral sites such as lips, tongue and palate, it is relatively unusual to find it in the nasal cavity. Furthermore, lesions normally involute spontaneously after childbirth. For persistent lesions requiring surgical management, imaging has historically been limited to CT. This case is notable not only for its uncommon location but also for its recurrent nature, failure to regress post partum and the use of MRI in the preoperative planning.

Revision Stapes Surgery: A Novel Technique of Overcoming Erosion of the Long Process of Incus Using Hydroxylapatite Cement and Shape Memory Piston.

BACKGROUND: Stapes surgery is performed to treat hearing loss in patients with otosclerosis. Erosion of the long process of incus can occur postoperatively and requires demanding revision surgery to further improve the hearing. The authors describe a novel method of performing revision stapes surgery where there is erosion of the long process of incus. METHODS: A retrospective case series analysis of a database of revision stapes operations performed by one surgeon between July 2013 and December 2017 at a tertiary center was carried out. 26 cases were identified where there was significant erosion of long process of incus. The ossicular chain in these cases was reconstructed using a novel technique of using cement to fix the piston prosthesis to the incus remnant. The full technique is described herein. The pre- and postoperative audiometric data were analyzed. RESULTS: Mean preoperative air bone gap (ABG) was 29.3 dB and mean postoperative ABG was 9.9 dB. Of the 22 patients with recorded postoperative masked bone conduction thresholds, 16 had ABG closure to < 10 dB (72.7%). CONCLUSION: We have shown highly favorable outcomes using this novel technique in addressing erosion of the long process of incus in revision cases for patients with otosclerosis.

UK medical students' perceptions, attitudes, and interest toward medical leadership and clinician managers.

BACKGROUND: We aimed to determine UK medical students' perceptions and attitudes and interest toward medical leadership and clinician managers. METHODS: A cross-sectional study was conducted during the academic year 2015-2016. An online questionnaire was distributed to 2,349 final-year students from 10 UK medical schools. Participants were asked to complete a 5-point Likert scale on their current perceptions, attitudes, and interest toward medical leadership and clinician managers. They were also asked to self-rate their leadership competences set by the Medical Leadership Competency Framework and to rate the quality of management and leadership training they received from their medical school. RESULTS: In total, we received 114 complete responses. Only 7.9% of respondents were in agreement (strongly agree or agree) when asked whether they felt they were well informed about what a managerial position in medicine entails. When asked whether clinicians should influence managerial decisions within a clinical setting, 94.7% of respondents were in agreement with the statement. About 85% of respondents were in agreement that it is important for clinicians to have managerial or leadership responsibilities, with 63.2% of students in agreement that they would have liked more management or leadership training during medical school. Over half the respondents rated their management and leadership training they received during medical school as "very poor" or "poor" (54.4%). CONCLUSION: Our study suggests that UK medical students have an appetite for management and leadership training and appreciate its importance but feel that the training they are receiving is poor. This suggests that there is a gap between the demand for management and leadership training and the quality of training supplied by UK medical schools.

Endourologic Management of an Iatrogenic Ureteral Avulsion Using a Thermoexpandable Nickel-Titanium Alloy Stent (Memokath 051).

Background: The use of ureteroscopy in the management of urolithiasis is well established. Ureteral avulsion is a rare but challenging complication of the procedure. Postureteral injury strictures are a common result of such injuries and are typically managed with reconstructive surgery or endoscopically with polymer stent. This case represents the first effective management of ureteral avulsion and subsequent ureteral stricture using a Memokath ureteral stent. Case Presentation: A 54-year-old gentleman presented to the Department of Urology with right loin pain as a result of right renal calculi, previously treated with extracorporeal shockwave lithotripsy. The patient was investigated with ultrasonography and noncontrast CT of his urinary tract, revealing mild right-sided hydroureteronephrosis and two right proximal ureteral stones, measuring 9 and 4 mm, respectively. He underwent a right semirigid ureteroscopy and laser stone fragmentation with complete stone clearance, but on withdrawal of the ureteroscope, a right ureteral injury occurred with ureteral mucosal avulsion extending from the L3/L4 vertebrae to the right vesicoureteral junction. Upon consideration of several options for management of this ureteral avulsion, the patient opted for endourologic stenting. After 10 months, the patient developed a ureteral stricture as a result of the avulsion. He was troubled with stent-related symptoms and wanted to avoid reconstructive surgery and, therefore, opted for a Memokath ureteral stent. The patient recovered well with excellent renal function and drainage on subsequent mercaptoacetyl-triglycyl renogram. Conclusion: Ureteral avulsion is a rare but important complication of ureteroscopy with numerous options available for management. Discussions should be had with the patient to weigh the various options, and metallic stents should be considered in the long-term management of such injuries and their sequel.

The surgical management of male breast cancer: Time for an easy access national reporting database?

INTRODUCTION: Male breast cancer is extremely rare with an incidence of less than 1% of all breast cancers. Literature reports a peak of incidence at roughly 71 years of age. Management currently follows the same clinical pathways as female breast cancer as a general rule. METHODS: A retrospective search for all patients who were referred and diagnosed with male breast cancer at our centre was undertaken. Patients notes were then explored for demographics, histological staging, multidisciplinary team meeting outcome and treatment. A literature search including the search terms 'Male Breast Cancer AND Surgery' or 'Male Breast Cancer AND Experience' were used. Non English language articles, or those without abstracts were excluded. RESULTS: Seven patients were reviewed over 3 years (2006-2009). Mean agea was 69 years and mean lesion size was 15 mm. Histology was invasive ductal carcinoma for all patients. All patients were ER receptor positive. Two patients were HER2 positive. Five patients were offered mastectomy. One patient refused treatment. In follow up at 36 months there were 3 recurrences. 1 patient was lost to follow up. There were 3 mortalities. The literature search identified 72 articles. Articles were subdivided into those that discussed the surgical management of male breast cancer (n = 8), articles that discussed male breast cancer as podium presentations or posters with no full text article publication (n = 13) and finally full text publications of case experience of male breast cancer (n = 21). DISCUSSION: We report a series of seven cases of male breast cancer encountered over three years, evaluating patient demographics as well as treatment and outcomes. In our series patients were managed with mastectomy. New evidence is questioning the role of mastectomy against breast conserving surgery in male patients. Furthermore there is a lack of reporting infrastructure for national data capture of the benefits of surgical modalities. Literature review highlights the varied clinical experience between units that remains reported as podium presentation but not published. The establishment of an online international reporting registry would allow for efficient analysis of surgical outcomes to improve patient care from smaller single centres. This would facilitate large scale meta analysis by larger academic surgical centres.

Systematic review of perioperative outcomes following laparoscopic abdominal aortic aneurysm repair.

OBJECTIVE: To collate information available in the literature regarding perioperative outcomes following elective laparoscopic abdominal aortic aneurysm repair. MATERIALS AND METHODS: Electronic databases were searched and a systematic review was performed. In total, 1256 abstracts were screened, from which 10 studies were included for analysis. Perioperative and technical outcomes were analysed. RESULTS: In the totally laparoscopic repair of infra-renal aneurysms (n = 302), 30-day mortality ranged between 0% and 6% and in the laparoscopic-assisted cases (n = 547) ranged between 0% and 7%. Of the former group, 5-30% of cases were converted to open repair, with 6% reintervention rate, whereas there was a 5-10% conversion and 3% reintervention rate in the latter group. CONCLUSIONS: The outcomes from selected patients in selected centres demonstrate that elective laparoscopic repair of aortic aneurysms is feasible and comparable in safety to open repair; it remains unclear, however, whether there are substantial advantages of this method compared with open and endovascular repair.

The Kv7.2/Kv7.3 heterotetramer assembles with a random subunit arrangement.

Voltage-gated K(+) channels composed of Kv7.2 and Kv7.3 are the predominant contributors to the M-current, which plays a key role in controlling neuronal activity. Various lines of evidence have indicated that Kv7.2 and Kv7.3 form a heteromeric channel. However, the subunit stoichiometry and arrangement within this putative heteromer are so far unknown. Here, we have addressed this question using atomic force microscopy imaging of complexes between isolated Kv7.2/Kv7.3 channels and antibodies to epitope tags on the two subunits, Myc on Kv7.2 and HA on Kv7.3. Initially, tsA 201 cells were transiently transfected with equal amounts of cDNA for the two subunits. The heteromer was isolated through binding of either tag to immunoaffinity beads and then decorated with antibodies to the other tag. In both cases, the distribution of angles between pairs of bound antibodies had two peaks, at around 90° and around 180°, and in both cases the 90° peak was about double the size of the 180° peak. These results indicate that the Kv7.2/Kv7.3 heteromer generated by cells expressing approximately equal amounts of the two subunits assembles as a tetramer with a predominantly 2:2 subunit stoichiometry and with a random subunit arrangement. When the DNA ratio for the two subunits was varied, copurification experiments indicated that the subunit stoichiometry was variable and not fixed at 2:2. Hence, there are no constraints on either the subunit stoichiometry or the subunit arrangement.