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.

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.

Betahistine Prescribing Practices in England: An Analysis of Prescribing and National Spending Pre- and Post-BEMED Trial.

OBJECTIVE: Betahistine has not been proven to be superior to placebo in the BEMED study, a multicenter, double-blind, randomized, placebo controlled trial. Our study aimed to establish the prescribing practices of clinicians in England in relation to betahistine and to assess if there has been any change in prescribing practices since the publication of the BEMED trial. STUDY DESIGN: Retrospective study and clinician survey. PATIENTS: All patients who were prescribed betahistine from primary care. MAIN OUTCOME MEASURE: Total quantity of betahistine prescribed and total actual cost. RESULTS: The average total monthly quantity prescribed was 11,143,253 tablets (range, 10,056,516-12,276,423). Prescribing did not decrease from the period before (January 2014-February 2016) to after (February 2016-February 2021) the publication of the BEMED trial, with the average monthly prescribing before publication being 11,294,848 tablets (range, 10,280,942- 12,276,423) and the average monthly prescribing after publication being 11,081,123 tablets (range, 10,056,516-11,915,707). The average actual monthly cost increased from the period before publication to after publication from a sum of £279,264.82 to a sum of £428,846.22. Most (90.5%) of the survey respondents prescribed betahistine for Menière's disease. Less than half (38.09%) prescribed betahistine for indications other than Menière's disease. Only 45.24% of the clinicians were aware of the results of the BEMED trial. CONCLUSIONS: Knowledge of the BEMED trial among otology and neurotology subspecialists is lacking. The results of the BEMED have made no difference to prescribing practice, and in fact, the cost of the medication to the health bill has increased.

Awareness of Human Papillomavirus (HPV) and HPV Vaccination amongst the General Population in Germany: Lack of Awareness and Need for Action.

INTRODUCTION: The oncogenic human papillomaviruses (HPV) types 16 and 18 contribute to more than 73% cases of all HPV-related cancers and commonly affect the anogenital and head and neck region, with rapidly rising incidence rates of HPV-related oropharyngeal squamous cell carcinomas (OPSCC). HPV vaccination has the potential to decrease the burden of HPV-related disease, but vaccination rates remain low in many countries. We investigated the level of awareness of HPV, and HPV-OPSCC in particular, in a representative sample of the German population. MATERIALS AND METHODS: As part of an online, population-based survey, an electronic questionnaire was administered to a representative sample of 1,095 adult individuals with a specific emphasis on awareness of HPV, transmission, and indicator symptoms of oropharyngeal cancer. Statistical analysis of levels of awareness and relation of these to age, gender, and socioeconomic background were conducted using the IBM SPSS Statistics Version 25.0. RESULTS: 699/1,095 (63.8%) subjects had never heard of HPV. Of the subjects with awareness for HPV, 210 knew that HPV could be transmitted during sex (58.3%) and 138 recognized HPV as a risk factor for OPSCC (14.2%), unrelated to gender (p = 0.357), educational status (p = 0.581), or family status (p = 0.719). 416 subjects knew that a preventive vaccine against HPV existed (44.9%). Women were significantly more aware of HPV (34.2% vs. 22.8%, p < 0.001) and the vaccination (56.4% vs. 32.7%, p < 0.001) as were men. Younger individuals (age group 25-34) were significantly more aware of HPV (p < 0.001), likely as they were offered and/or had received the HPV vaccination. There was no regional variation of HPV awareness within the German state (p = 0.051). CONCLUSION: Here we demonstrate a significant lack of awareness of HPV and HPV vaccination in a representative sample of the German population. Levels of awareness of the link of HPV and oropharyngeal cancer are particularly low, bearing in mind that this cancer is commonly affecting men and incidence rates are rapidly rising in many European countries and the USA. Awareness programs and further education are required to tackle the low awareness rates and increase the uptake of the vaccination program not only in Germany, but also worldwide.

The changing face of paediatric airway endoscopic surgery: An 8-year single surgeon review.

INTRODUCTION: As a recently established division, we sought to reflect on the development of our paediatric airway surgery service, and prospectively examine the diagnoses that underwent microlaryngobronchoscopy (MLB) to help quantify the evolving population demographics of paediatric airway disorders. MATERIAL AND METHODS: This was a prospective longitudinal study conducted of all paediatric MLBs performed by a single surgeon in a tertiary paediatric ENT centre between 2012 and 2019. RESULTS: A total of 1040 MLBs were performed in 498 patients at the paediatric ENT centre of the Royal London Hospital. Median age at first procedure was 19 months. Median follow-up was 48 months. Primary diagnoses were laryngomalacia (21%), subglottic stenosis (SGS - 18%), laryngeal cleft (13%), and normal anatomy (28.3%). Repeat procedures were needed in 39.1% patients, who underwent a median of 2 repeat procedures. SGS (57.7%) constituted majority of the repeat category, followed by laryngeal cleft (12.36%), laryngomalacia (10.15%), unilateral/bilateral vocal cord palsy(4.24%) and laryngeal papilloma(4.24%). Laryngeal papilloma constituted largest number of procedures per patient (Median = 4, IQR = 5.75), followed by subglottic web and SGS. Mean length of stay(LOS) was 0.67 ± 0.96 days(d), with laryngeal cleft cases recording longest mean LOS. There was a steady increase in proportion of day-surgeries across study period [6.9% (2012) vs 59%(2019)]. CONCLUSION: SGS constitutes the major bulk of paediatric airway surgery, reflective of increasing number of premature births and prolonged intubation among neonates. Day-case MLB is a safe and feasible option in selected patients. This long-term data provides useful information to accurately prognosticate patients regarding potential number of repeat procedures for each diagnosis.

The role of antibiotics in the surgical management of paediatric obstructive sleep apnoea (OSA): a cohort study.

PURPOSE: Obstructive sleep apnoea (OSA) describes an irregular night-time breathing pattern that is present in approximately 1.8% of children and can have a negative impact on quality of life. The use of antibiotics postoperatively is controversial. They are commonly prescribed; however, they can also be associated with side effects and resistance. This study explores the role of antibiotics in the post-operative management of children with OSA in a cohort of children. METHODS: We conducted a retrospective cohort study of children undergoing surgery for OSA or sleep disordered breathing (SDB) at a tertiary paediatric ENT referral centre from November 2018 to November 2019. RESULTS: This study identified 382 children who had undergone surgical treatment for OSA or sleep disordered breathing (SDB); 319 underwent adenotonsillectomy, 53 adenoidectomy and 10 tonsillectomies. Antibiotics were given post-operatively to 158 (41%) patients and 18 (11%) of these patients presented to hospital with post-operative complications. A higher number of patients re-presented to hospital from the group who did not receive antibiotics (p = 0.982). Bleeding (p = 0.886) and infection (p = 0.823) were also more common in those children who did not receive antibiotics. CONCLUSION: Antibiotics led to fewer complications and re-presentations to hospital in children undergoing operative management of OSA; however, this trend was not found to be statistically significant.

Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy.

Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies. Even in high-income countries the 5-year survival rate for stage IV NPC is less than 40%. Here we report high somatostatin receptor 2 (SSTR2) expression in multiple clinical cohorts comprising 402 primary, locally recurrent and metastatic NPCs. We show that SSTR2 expression is induced by the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) via the NF-κB pathway. Using cell-based and preclinical rodent models, we demonstrate the therapeutic potential of SSTR2 targeting using a cytotoxic drug conjugate, PEN-221, which is found to be superior to FDA-approved SSTR2-binding cytostatic agents. Furthermore, we reveal significant correlation of SSTR expression with increased rates of survival and report in vivo uptake of the SSTR2-binding 68Ga-DOTA-peptide radioconjugate in PET-CT scanning in a clinical trial of NPC patients (NCT03670342). These findings reveal a key role in EBV-associated NPC for SSTR2 in infection, imaging, targeted therapy and survival.

Squamous cell cancer of the temporal bone: a review of the literature.

BACKGROUND AND AIMS: Squamous cell carcinoma (SCC) of the temporal bone is a rare malignancy accounting for only 0.2% of head and neck cancers. There is currently no clear consensus on staging or common approach to management. It is the aim of this work to provide the readers with a review of the current literature on this malignancy. METHODS: A literature review was performed identifying 16 case series with patient numbers ranging from 12 to 124. A total of 708 patients were included in this review, 67% presented with advanced disease. 578 cases were managed operatively with lateral temporal bone resection, some underwent local resection alone in early stage disease. In all studies radiation therapy was used as an adjunct to some degree. RESULTS: More than half of studies reported 100% either 2-, 3- or 5-year survival for T1 and T2 disease with no nodal involvement. Survival correlated with disease stage and in five studies SCC differentiation was found to be a significant prognostic factor. Post-operative radiotherapy was found to improve survival in only one study. CONCLUSIONS: Temporal bone SCC is a readily treatable malignancy in early stage disease, however late stage disease has a poor prognosis. Differentiation of the SCC and stage of disease at presentation appear to have the greatest influence on 5-year survival rates. Further work is required in both the identification of early stage disease and in the treatment of later T3 and T4 lesions.

Intratympanic Steroid Use for Sudden Sensorineural Hearing Loss: Current Otolaryngology Practice.

OBJECTIVE: To investigate the current practice of intratympanic steroid (ITS) injection for sudden sensorineural hearing loss (SSNHL) in the United Kingdom and link the data with data from the United States and continental Europe. METHODS: A survey of 21 questions was distributed to members of the British Society of Otology using an online survey platform via ENT UK. Data obtained from UK otolaryngologists (n = 171) were integrated with previously published data from other countries, including the United States (n = 63) and continental Europe (n = 908). RESULTS: In the United Kingdom, 62% of responding otolaryngologists use ITS injection for SSNHL, while 38% do not. Of those using ITS, 59% use it as first-line treatment, either using it in conjunction with oral steroids (51%) or using it as monotherapy (8%). Of those that use ITS, a majority (83%) use it as salvage therapy when primary treatment with systemic steroids has failed, and similar results are found in the continental Europe and US surveys. The most commonly used preparation is dexamethasone. Responses to questions regarding treatment regimes used are enlightening and show considerable variation in the treatment regimes used within and between countries. CONCLUSIONS: There is a wide variation in practice with regards to ITS for SSNHL hearing loss in the United Kingdom, United States, and continental Europe. In the absence of protocols or definitive guidance from published literature, knowledge of contemporary practice may help guide or encourage reevaluation of clinical practice and will help guide the design of future clinical trials.

Clinical Subtyping of Ménière's Disease.

Fundamentally, Ménière's disease is a constellation of symptoms and, as such, may represent the final common pathway for a number of disease processes, as opposed to being the consequence of a single isolated pathology. Within this type of consideration, much can be learned regarding the etiology, presentation, prognosis, and treatment of these individual conditions by applying subtyping techniques currently employed to better understand similar disease processes that are encountered in other allied fields of medicine. This commentary proposes the principles, required processes, and benefits of subtyping for Ménière's disease.

Otorhinolaryngology and Diving-Part 1: Otorhinolaryngological Hazards Related to Compressed Gas Scuba Diving: A Review.

IMPORTANCE: Scuba diving is becoming increasingly popular. However, scuba diving is associated with specific risks; 80% of adults and 85% of juvenile divers (aged 6-17 years) have been reputed to have an ear, nose, or throat complaint related to diving at some point during their diving career. Divers frequently seek advice from primary care physicians, diving physicians, and otorhinolaryngologists, not only in the acute setting, but also related to the long-term effects of diving. OBSERVATIONS: The principles underpinning diving-related injuries that may present to the otorhinolaryngologist rely on gas volume and gas saturation laws, and the prevention of these injuries requires both that the diver is skilled and that their anatomy allows for pressure equalization between the various anatomical compartments. The overlapping symptoms of middle ear barotrauma, inner ear barotrauma, and inner ear decompression sickness can cause a diagnostic conundrum, and a thorough history of both the diver's symptoms and the dive itself are required to elucidate the diagnosis. Correct diagnosis and appropriate treatment result in a more timely return to safe diving. CONCLUSIONS AND RELEVANCE: The aim of this review is to provide a comprehensive overview of otorhinolaryngological complications during diving. With the increasing popularity of diving and the frequency of ear, nose, or throat-related injuries, it could be expected that these injuries will become more common and this review provides a resource for otorhinolaryngologists to diagnose and treat these conditions.

Otorhinolaryngology and Diving-Part 2: Otorhinolaryngological Fitness for Compressed Gas Scuba Diving: A Review.

IMPORTANCE: Self-contained underwater breathing apparatus (scuba) diving has become increasingly popular with millions of people diving each year. Otorhinolaryngologists are often consulted either by patients or diving physicians regarding fitness to dive, and at present, the guidelines do not provide comprehensive information regarding the evaluation of this patient cohort. The aim of this review is to provide a comprehensive overview of existing otorhinolaryngological guidelines for fitness to dive recreationally. OBSERVATIONS: There is a paucity of guidelines for assessing otorhinolaryngological fitness to dive in the recreational diver. Comprehensive guidelines exist from US, European, and UK regulatory bodies regarding fitness for commercial diving; however, not all of these can be directly extrapolated to the recreational diver. There are also a variety of conditions that are not covered either by the existing fitness for recreational diving guidelines or the commercial regulatory bodies. CONCLUSIONS AND RELEVANCE: With the paucity of recreational fitness to dive guidelines we must draw on information from the commercial diving regulatory bodies. We have provided our own recommendations on the conditions that are not covered by either of the above, to provide otorhinolaryngologists with the information they require to assess fitness for recreational diving.

Evaluation of a newly introduced tonsillectomy operation record for the analysis of regional post-tonsillectomy bleed data: a quality improvement project at the London North West Healthcare NHS Trust.

The primary objective of this audit and quality improvement project was to retrospectively analyse regional post-tonsillectomy haemorrhage data as per national recommendations. However, this process highlighted the need for high-quality routinely collected data; something that was not always available via retrospective audit and thus does not enable formal aetiological factor analyses. We therefore created further secondary objectives to facilitate our primary audit objective. These secondary objectives were (1) to introduce a standardised tonsillectomy operation proforma to improve completeness and quality of routinely collected data and (2) to evaluate and validate proforma use and usefulness in improving using routine data collection to help with a repeated audit of post-tonsillectomy haemorrhages with the eventual aim to help improve operative outcomes by identifying potential associated factors. The retrospective audit component, the prospective audit and the quality improvement component were all carried out at the Northwick Park Hospital and Central Middlesex Hospital (London North West Healthcare NHS Trust). First, 642 tonsillectomy records (2012-2014) were retrospectively reviewed. Free-text operative documentation and, where possible, potential factors associated with post-tonsillectomy haemorrhages were analysed. In addition, completeness of data available before and after the introduction of (A) a new paper-based and (B) electronic surgical record proforma was reviewed (2014-2015). Over a 2-year period, 62 of the 642 (9.7%) audited tonsillectomy patients had a post-tonsillectomy haemorrhage, and 19 of these (2.9%) had to return to theatre for surgical arrest of the haemorrhage. Bipolar diathermy was the most commonly used technique. During this period, data available from routine operative documentation in the surgical operation notes were variable and thus did not allow identification of potential factors associated with post-tonsillectomy haemorrhage. The completeness and quality of data significantly improved after the introduction of a standardised paper-based proforma with sections for required details based on known risk factors for post-tonsillectomy haemorrhage and required operative details. Quality and completeness of data was further improved after the introduction of an electronic version. This electronic proforma will allow prospective spiral auditing results, early identification of raised bleeding rate, and provide individual surgeon audit results.

Do postoperative NSAIDs improve breast cancer outcomes? A Best Evidence Topic.

A Best Evidence Topic was undertaken to systematically review the evidence regarding the use of NSAIDS in breast cancer patients. The search strategy generated 149 titles, of which six were best placed to answer the clinical question. These included three prospective cohort studies, two retrospective cohort studies and one case control study, examining a total of 18,415 breast cancer patients. The study methodologies were highly variable and all relied on approximate measures of NSAID consumption. There is limited evidence that use of aspirin and non-aspirin NSAIDs may be associated with decreased breast cancer mortality and all-cause mortality in patients diagnosed with breast cancer. Optimum type and dosage of NSAID for this purpose remains unclear. There is a need for large-scale randomised controlled trials to further clarify.

Unexpected change in charge transfer behavior in a cobalt(II) porphyrin-fullerene conjugate that stabilizes radical ion pair states.

Two cobalt(II) porphyrin-C(60) malonate-linked conjugates, the mono-connected Co1 and the bis-connected trans-2 isomer Co3, have been synthesized for the first time either by direct cyclopropanation with the precursor malonate Co4 or by metalation of the bisadduct H(2)3. For the investigation of the interaction between the porphyrin donor and fullerene acceptor within these dyads, electrochemical and photophysical investigations have been carried out. Compared to Zn3 and trans-2 bisadduct 7, the first reduction of the fullerene moiety within Co3 becomes easier (40 mV in dichloromethane and 20 mV in benzonitrile), indicating significant interactions between the pi-system of the fullerene and the d-orbitals of the central Co atom. Compared to the Co complexes 9, Co4, and Co1, the first oxidation of Co3 is considerably shifted to more positive potentials, if benzonitrile instead of dichloromethane is used as solvent. At the same time, the oxidation is no longer centered on the Co(II) center but on the porphyrin macrocycle, as corroborated by spectroelectrochemistry. A similar solvent dependence was observed in transient absorption spectroscopic measurements. In toluene, benzonitrile and anisole photoinduced electron transfer within Co3 leads to the formation of a charge-separated state Co(II)P.+ -C(60).- with a lifetime of 560 +/- 20 ns in benzonitrile, whereas in other solvents such as THF, nitrobenzene, ortho-diclorobenzene, and tert-butylbenzene the formation of a Co(III)P-C(60).- as transient was detected, which is, however, short-lived (860 +/- 40 ps in THF) and exhibits charge recombination dynamics that are in the Marcus inverted region. Particularly important is the fact that the electronic coupling (V) in Co(III)P-C(60).- is 18 cm(-1) substantially smaller than the V value of 313 cm(-1) in ZnP.+ -C(60).- .

Tris(thioacetals) from benzene hexathiol: towards covalent self-assembly.

Mixtures of isomers are available from the reaction of benzene hexathiol with three equivalents of p-tolualdehyde and kinetic traps avoided under the reported catalytic conditions, establishing tris(thioacetals) as potential building blocks for covalently self-assembled complex structures.