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Purpose: To examine patient-centred outcome following endoscopic treatment of central airway stenosis in terms of days alive and out of hospital (DAOH), need for re-intervention, and complications, with reference to aetiology of disease and applied treatment methodology., Methods: Analyses were based on data from consecutive adult patients treated endoscopically for benign central airway obstruction at Aarhus University Hospital from 2012 to 2022, with a minimum follow-up of one year. DAOH was calculated for 30 and 365 days. Complications were graded based on the Clavien-Dindo classification. Univariate and multivariate analyses were performed to identify predictors for DAOH, re-intervention and complications., Results: 82 consecutive adult patients underwent endoscopic treatment during the period of inclusion, comprising a total of 175 dilatations, 42 benign tumour resections, and 67 stent insertions. Multiple interventions and short re-intervention intervals was more likely amongst patients reporting significant preoperative dyspnoea or requiring preoperative respiratory support, as well as patients treated with endoscopic insertion of silicone stents. The overall complication rate per procedure was 11.7%, and complications were more likely to occur in patients with high age, high BMI and comorbidity. Overall DAOH during the first year after intervention was 343 days, lowest amongst patients with tracheobronchomalacia or severe airway stenosis, and in those who underwent endoscopic stent insertion., Conclusion: Endoscopic treatment is a safe and viable intervention in the management of benign central airway obstruction in adults with few complications and a high overall outcome., Competing Interests: Declarations. Ethical approval: The study was authorised by the ethics committee of the Central Denmark Region. Permit 1-45-70-16-23. This approval waivered the need for consent for inclusion and publication. Conflict of interest: The authors of this article have no conflicts of interest to declare., (© 2025. The Author(s).)

Background: Diagnostic and therapeutic management of patients with head and neck squamous cell carcinoma of unknown primary (HNSCCUP) remains a challenge. The aim of the present phase IV study was to assess adherence to the current Danish guidelines and evaluate the treatment outcome in HNSCCUP patients., Materials and Methods: Prospectively collected data in the DAHANCA database from patients treated between 2014 and 2020 was evaluated. The median follow-up was 6.7 years. Treatment included definitive neck dissection (dND), primary (chemo-)radiotherapy ((C-)RT), neck dissection (ND) followed by postoperative (C-)RT (ND + (C-)PORT). Outcome were reported as five-year estimates of loco-regional failure (LRF), ultimate LRF (ULRF), disease specific mortality (DSM), overall survival (OS), and toxicity scores ≥ 3., Results: A total of 288 patients were treated, of which 254 (88 %) received treatment with curative intent and were eligible for adherence assessment. These were allocated to dND (n = 60), (C-)RT (n = 81) and ND + (C-)PORT (n = 113). The HPV/p16 status was known in 94 % of patients with 109 (43 %) positive cases. The 5-year LRF, DSM, and OS for patients treated with curative intent was 22 %, 15 % and 73 %, and in patients with p16 positive disease 16 %, 5 %, and 85 %. The overall guideline adherence was 76 % (192/254). In the adherent group the LRF, ULRF, DSM, and OS were 22 %, 11 %, 16 %, and 73 %, respectively., Conclusion: The study revealed good treatment outcome measures in HNSCCUP patients subject to the Danish guidelines, comparable to other head and neck cancer patients. The observed guideline-deviations did not affect outcome., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Diagnosis of subglottic stenosis remains greatly a challenge for physicians due to case rarity and presentation of symptoms imitating several other more prevalent medical disorders. Idiopathic subglottic stenosis most often occurs in previously healthy perimenopausal Caucasian women. Several cases have reported symptom progression and increased stenosis, during or in between pregnancies in younger women. The following case of a 32-year-old woman provides an example of significantly long duration from initial symptom onset to diagnosis of idiopathic subglottic stenosis. Additionally, the case illustrates how pregnancy complicates diagnosis and due to the potential risk of stenosis progression and complications during labour, the patient had to undergo surgery with balloon-dilation at week 17 of pregnancy., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2025 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Purpose: To examine the outcome of palliative endoscopic treatment of malignant central airway obstruction (CAO) and identify predictors for Days Alive and Out of Hospital (DAOH), overall survival and treatment related complications., Methods: Consecutive adult patients treated endoscopically for malignant CAO at Aarhus University Hospital from 2012 to 2022 were included in the study. Statistical analyses were carried out to identify predictors for DAOH, survival and complications., Results: 127 consecutive patients met the inclusion criteria. The majority of patients were categorised with stage IV lung cancer, the majority being males, with a median age of 67 years. The endoscopic interventions were mainly tumour debulking combined with airway stent insertion or tumour debulking alone. The complication rate was 21.0% and the mortality rate was 3.9%. In total, 89.8% of the patients experienced symptom relief following surgery, and the majority (92.1%) were discharged from hospital within two days after intervention. Mean survival time following intervention was 144 days, mean DAOH 30  was 20.8 and mean DAOH 365  was 157. Survival was associated with comorbidity, type of intervention, preoperative respiratory support and postoperative oncologic treatment. A high preoperative ASA-score, preoperative respiratory support, urgency of intervention, female gender and insertion of airway stent were predictors for a poorer DAOH-outcome., Conclusion: Endoscopic palliative treatment of malignant CAO is generally feasible and safe, offering symptom relief in most cases. The method is considered an effective measure for short to median term palliation of respiratory distress., Competing Interests: Declarations. Ethics approval and consent to participate: The study was authorised by the ethics committee of the Central Denmark Region. Permit 1-45-70-16-23. This approval waivered the need for consent for participation and publication from included patients. Consent for publication: The study was authorised by the ethics committee of the Central Denmark Region. Permit 1-45-70-16-23. This approval waivered the need for consent for participation and publication from included patients. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Squamous cell carcinoma of unknown primary in the head and neck (HNSCCUP) remains a diagnostic challenge. Tongue base mucosectomy by transoral robotic surgery (TORS-TBM) can increase the diagnostic yield and de-intensify treatment. However, the added value of TORS-TBM as an adjunct to work-up programs for HNSCCUP is unclear. Furthermore, the optimal extent of the procedure and selection criteria remain to be established., Aim: The primary aim of the present study was to assess the diagnostic yield of TORS-TBM as a supplement to a standardized work-up program, using the Danish national guidelines as an example. Secondary aims include predictive values of HPV-testing and PET/CT., Methods: This was a national multicenter observational cohort study including all patients diagnosed with HNSCCUP from January 2013 to December 2019, who subsequently underwent TORS-TBM. In most cases HPV status was based on dual testing (p16 and HPV-DNA). Predictive values of PET/CT and HPV status were calculated., Results: A total of 100 consecutive patients underwent TORS-TBM; 93 total TBMs and 7 unilateral TBMs. The primary tumor was detected in 49 % (49/100) of patients. The detection rate was 58 % (47/81) in patients with HPV-associated disease (PPV of HPV status) and 11 % (2/19) in patients with HPV-independent disease. The NPV of HPV status was 89 %. The PPV and NPV of PET/CT was 53 % and 52 %, respectively., Conclusion: Adding total TORS-TBM to the current Danish guideline-based work-up program on HNCCCUP patients with HPV-associated disease significantly improved the diagnostic yield., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Determine participants' satisfaction with rehabilitation following total laryngectomy (TL) and investigate associations between dysphagia, voice problems, and possible explanatory variables., Methods: 172 Danish and Swedish participants having received a TL 1.6-18.1 years ago for laryngeal/hypopharyngeal cancer answered a questionnaire regarding satisfaction with rehabilitation following TL and the V-RQOL, MDADI, and HADS questionnaires., Results: 85% and 75% were satisfied with the help received from their local hospital and municipality, respectively. 22%, 78%, and 65% indicated having not received any vocal, swallow, or olfactory rehabilitation, respectively. MDADI mean score was 77.5, V-RQOL was 62.8 and the HADS questionnaire indicated that possible depression or anxiety was present in 16% and 20% of participants, respectively. Multivariate analysis found the following variables to be associated with dysphagia; more voice problems, higher depression score, higher anxiety score, and being treated and rehabilitated in Denmark vs. in Sweden. Furthermore, multivariate analysis found the following variables to be associated with voice problems; more problems with dysphagia and higher depression score., Conclusion: We found that the majority of participants were satisfied with the received rehabilitation but that a large proportion reported having no dysphagia or olfactory rehabilitation. We found that voice problems, dysphagia, and depression after TL are tightly linked, and therefore suggest that medical personnel in contact with TL patients should be aware of possible psychological late effects. We found that being treated and rehabilitated in Sweden, vs. in Denmark, was associated with a better swallow outcome and we suggest additional centralization of rehabilitation in especially Denmark., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Operation with a 3D exoscope has recently been introduced in clinical practice. The exoscope consists of two cameras placed in front of the operative field. Images are shown on a large 3D screen with high resolution. The system can be used to enhance precise dissection and provides new possibilities for improved ergonomics, fluorescence, and other optical-guided modalities., Methods: Initial experience with the ultra-high-definition (4K) 3D exoscope in thyroid and parathyroid operations. The exoscope (OrbEye TM ) was mounted on a holding system (Olympus)., Results: We used the exoscope in parathyroidectomy (N = 6) and thyroidectomy (N = 6). Immediate advantages and disadvantages were discussed and recorded. The learning curve for use of the exoscope may be shorter for surgeons with training in endoscopic or robotic procedures. There may be improved ergonomics compared with normal open-neck operations. Further, the optical guided operations can be used with fluorescence and have potential for different on-lay techniques in the future. The 4 K 3D image quality is state-of-art and is highly appreciated during fine surgical dissection and eliminates the need for loupes., Conclusion: In several ways, using the ORBEYE™ in thyroid and parathyroid surgery provides the surgical team with a new and enhanced experience. This includes improved possibility for teaching, surgical ergonomics, and a 4K 3D camera with a powerful magnification system. However, it is not clear if utilization of these features would improve surgical outcomes. Furthermore, the ORBEYE™ lacks incorporation of parathyroid autofluorescence, and the current costs for the system do not facilitate general access to exoscope assisted operations., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This study protocol for a prospective, multicenter, diagnostic, clinical trial describes the integration of transoral and transcervical ultrasonography (US) in the initial clinical work-up of patients referred to tertiary head and neck cancer centers with suspected oropharyngeal cancer. The study evaluates the blinded detection rate of oropharyngeal tumors and their US-estimated size and T-stage before histopathology and cross-sectional imaging are available. Magnetic resonance imaging (MRI) scans will be prospectively rated while blinded to T-site histopathology and US. The primary outcome measures of diagnostic accuracy, including sensitivity, specificity, positive and negative predictive values, and overall accuracy, will be reported for both US and MRI. A sub-analysis of prospectively rated 18F-Fluorodeoxyglucose (FDG) positron emission tomography/computerized tomography (PET/CT) scans in patients with clinically suspected unknown primary tumors will also be compared to US and MRI. Secondary outcome measures, including a comparison of tumor size estimation between US, MRI, and CT, will also be reported. This prospective multicenter study will provide clinically impactful information regarding the use of transoral and transcervical US for the diagnostic work-up of oropharyngeal cancer.

Purpose: To examine the role of the silicone stent in palliation of malignant central airway obstruction and identify potential preprocedural predictors for postprocedural outcome., Methods: Patients treated with endoscopic insertion of tracheobronchial silicone stents for malignant central airway obstruction at Aarhus University Hospital from 2012 to 2022 were identified from electronic medical records. Statistical analyses were carried out to identify factors affecting Days Alive and Out of Hospital, complications and overall survival., Results: 81 patients underwent a total of 90 tracheobronchial stent insertions. Days Alive and Out of Hospital (DAOH) for the first 30 days were affected negatively by urgent intervention, p < 0.001, preprocedural non-invasive respiratory support, p < 0.001, and preprocedural intubation, p = 0.02. Post-procedural oncological treatment was associated with a significant improved DAOH, p = 0.04. Symptomatology and lesion characteristics were not significantly associated with any impact on DAOH. Overall survival was poor (mean survival was 158 days), and only significantly affected by severe degree of dyspnea, p = 0.02, and postprocedural oncological treatment, p < 0.001. Complication where registered in 25.6% of cases within the first 30 days was observed. Procedure-related mortality was 3.7%. Based on chart annotations by an ENT-surgeon, 95% of the patients experienced relief of symptoms following stent insertion., Conclusions: Palliative tracheobronchial airway stenting with silicone stents is found to have a beneficial impact, more research is required for identification of predictors for postprocedural outcome based on preprocedural classifications., (© 2024. The Author(s).)

Background: Pain is prevalent after most TransOral Robotic Surgery (TORS) procedures and may limit function i.e. swallowing. Currently, there is limited knowledge regarding optimal pain treatment in TORS., Aims/objectives: This clinical trial randomized patients to either a high-dose dexamethasone or low-dose dexamethasone treatment in addition to a multimodal basic analgesic protocol. The aim of the trial was to investigate the pain intensity during rest and swallowing using the Visual Analogue Scale (VAS) after TORS lingual tonsillectomy. Secondary outcomes were acceptable food consistency, nausea, vomiting, opioid rescue usage, length of hospitalization, feeding tube placements, readmissions, blood glucose levels and postoperative complications., Methods: The trial was conducted between August 2020 and October 2022. Eligible patients were patients scheduled for TORS-L treatment of obstructive sleep apnea syndrome or as part of the diagnostic work-up of head and neck carcinoma of unknown primary., Results: Eighteen patients were and randomized 1:1. There were overall no significant differences between groups in the reported VAS scores during rest or swallowing ( p  ≥ .05). Overall, there were no differences in the secondary outcomes., Conclusion: There were no differences in the pain intensity in the two treatment groups allocated to a basic multimodal analgesic package and either high-dose dexamethasone or low-dose dexamethasone treatment. The trial is the first RCT to include pain measurement during a procedure-relevant activity, thus creating a platform for future recovery studies.

Background: The reported hospital length of stay (LOS) following transoral robotic surgery lingual tonsillectomy (TORS-L) is variable, with limited understanding of the factors requiring hospitalization and no evidence-based criteria for discharge., Aims/objectives: This observational cohort study investigated factors hindering discharge following TORS-L in a well-defined postoperative care program., Methods: Patients were included between August 2020 and October 2022. A discharge scheme was filled out twice daily, specifying the factor(s) for hospitalization among patients undergoing TORS-L. This trial was a sub-investigation of a national multicentre randomized clinical trial (RCT) testing the efficiency of high-dose dexamethasone on postoperative pain control. Participation in the RCT demanded admission to the fourth postoperative day as dexamethasone/placebo was given intravenously in repeated dosages till day 4 postoperatively., Results: Eighteen patients were included in the analysis. The main factor for hospitalization was nutritional difficulties, while pain was a limiting factor for discharge only on the first postoperative 1-3 days. More than half of the patients could have potentially been discharged on postoperative day 2 when omitting the RCT treatment plan in the analysis., Conclusion: The study estimates that the majority of patients may be discharged on postoperative day 2 following TORS-L.

Voice problems, also called hoarseness or dysphonia, can cause significant morbidity with communication difficulties and social isolation. This review summarises the causes and treatment of voice problems. Common causes of voice problems are related to inflammation, non-physiological usage of the voice, benign lesions of the vocal cords and damage to the nerves innervating the larynx. Nonetheless, it is important to keep malignancy in mind as a differential diagnosis. Referral to an otorhinolaryngologist is recommended for voice problems in adults with a duration of more than two weeks.

Objectives/hypothesis: The aims were to determine health-related quality of life (HRQoL), including voice problems, dysphagia, depression, and anxiety after total laryngectomy (TL), and investigate the associations between HRQoL and the late effects., Study Design: Cross-sectional study., Methods: 172 participants having received a TL 1.6 to 18.1 years ago for laryngeal/hypopharyngeal cancer filled in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire, Core and Head and Neck module (EORTC QLQ-C30, EORTC QLQ-H&N35), Voice-Related Quality of Life questionnaire (V-RQOL), M.D. Anderson Dysphagia Inventory (MDADI), and Hospital Anxiety and Depression Scale (HADS) questionnaires., Results: Participants scored worse than normative reference populations on all scales/items of the EORTC questionnaires, except one, and almost half of the scales/items showed a clinically relevant difference. Moderate/severe dysphagia was present in 46%, moderate/severe voice problems in 57%, depression in 16%, and anxiety in 20%. Decreasing age, increasing numbers of comorbidities, increasing voice problems, increasing dysphagia, and increasing depression symptoms, were associated with a lowered EORTC QLQ-C30 summary score., Conclusion: A substantial proportion of participants experienced clinically significant late effects and increasing levels of these were associated with a lowered HRQoL., Level of Evidence: 3 Laryngoscope, 132:980-988, 2022., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Prolonged healing of tracheostomy after decannulation has a negative impact on respiration, hygiene, cosmetics, and social life. Even so, evidence-based observations of tracheostoma healing time are lacking. Therefore, the aim of this study was to determine tracheostomy wound healing time after decannulation., Methods: In this prospective observational cohort study, we included 30 subjects undergoing decannulation following prolonged mechanical ventilation via tracheostomy. Our primary endpoint was tracheostomy healing time defined as time from decannulation to airtight healing. To identify any factors related to healing time, we included information about patient demographics, comorbidities, tracheostomy method, tube size, and intubation time. All subjects were observed daily until their tracheostomy wound had healed., Results: The median tracheostomy healing time was 6.5 (1-22) days. The duration of tracheal cannulation was the only factor significantly correlated with prolonged healing (p=0.03). Four patients were subjected to recannulation shortly after decannulation due to hypercapnia, respiratory failure, secretion accumulation, or self-decannulation. All wounds achieved complete spontaneous airtight closure., Conclusions: Duration of spontaneous tracheostomy closure after decannulation was 1-22 days, and closure time correlated with duration of cannulation., (©Copyright: the Author(s).)

Purpose: Combined use of contact endoscopy (CE) and Narrow Band Imaging (NBI, Olympus ® ) is suggested for the visualization of specific vascular changes indicative of glottic neoplasia. We investigated the interrater reliability and agreement in 3 recognized classification systems of vascular changes applied to images from CE + NBI in patients suspected for glottic neoplasia., Methods: Six experienced head and neck surgeons familiar with NBI rated 120 images obtained by CE + NBI by 3 classification systems of vascular changes as suggested by Ni et al. (N-C), Puxeddu et al. (P-C), and the European Laryngological Society (ELS-C). Three raters were experienced in CE, and three raters had only limited experience with CE. Crude agreement and Fleiss' kappa with 95% confidence interval were estimated for all 6 raters, and for the 2 levels of expertise for each original classification system and for dichotomized versions of the N-C and the P-C based on suggested neoplastic potential., Results: The interrater crude agreement and the corresponding kappa values for the ELS-C were good and significantly higher than those for the N-C and P-C for all raters, irrespective of the level of experience with CE (p < 0.0001). There were no significant differences between the N-C and the P-C (p = 0.16). Kappa was considerably improved for both the N-C and the P-C to a level not different from the ELS-C (p = 0.21-0.71) when their 5 original categories were pooled into dichotomized classifications., Conclusion: Difficulties in reliably classifying vascular changes in CE + NBI are evident. Two-tier classification systems are the most reliable.

Objectives: Glottic precursor lesion (GPL) is a well-known premalignant condition, but the existing knowledge of incidence and malignant potential is based on subpopulation studies. In this first, nationwide study we report data from all verified cases of GPL in Denmark during a 10-year period with focus on incidence and malignant transformation of GPL. Methods: Patients were identified by a search for GPL in the time period from 01.01.2000 to 31.12.2009 using the Danish Pathology Data Base, Patobank, which is a nationwide source of all cyto- and histopathological data obtained in Denmark. Data were validated and supplemented by medical chart review. Results: A 10-year national cohort of 965 patients (median age 60 years, male-female ratio 2:1) with histologically verified GPL was analyzed. The overall malignant transformation rate was 18.3% (mild dysplasia 7.7%, moderate dysplasia 19.8%, severe dysplasia 28.5%, and carcinoma in situ 40.3%) with a median progression time of 29 months. Eighty-eight percent of patients were active or former smokers. A significantly larger proportion of male patients (24.1%) experienced malignant transformation compared to females (6.6%) ( p  < .001). Conclusion: This nationwide population-based study of GPL patients confirmed a stable incidence of GPL in Denmark from January 2000 to December 2009 and a considerable malignant potential, correlated to the grading of GPL according to the World Health Organization classification of laryngeal precursor lesions from 2005, WHOC2005. The recent update, WHOC2017, of low-grade versus high-grade lesions may thus contain less nuanced prognostic information than WHOC2005. Level of evidence: 2b retrospective cohort study.

This case report presents an elderly male patient who on diagnosis with a large oropharyngeal tumour had no specific symptomatology apart from severe obstructive sleep apnoea. Histopathology revealed the tumour to be an adult rhabdomyoma, a rare but benign tumour arising from striated muscle cells. The tumour obstructed most of the oropharyngeal space and almost occluded the patient's airway when lying in a supine position. The patient was deemed operable, and the tumour was excised in toto using a transoral robotic surgery system. On follow-up, the patient had a severe reduction of apnoeas/hypopnoeas and felt subjectively 'reborn'. This is to our knowledge the first case where an adult rhabdomyoma is removed using a robot-assisted approach, thus presenting a new and viable option when considering removal of benign tumours of the pharynx leading to a very minor degree of morbidity for the patients., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To evaluate the individual and combined ability of videostroboscopy (VS), high-speed digital imaging (HSDI), enhanced endoscopy (EE) and saline infusion (SI) to predict neoplasia, defined as glottic precursor lesion (GPL) or T1a glottic cancer, in patients suspected for glottic neoplasia., Methods: A nationwide prospective cohort study of patients treated by cordectomy for suspected GPL or T1a glottic cancer from August 1st 2016 to October 31st 2018 was conducted in the five Danish University Departments of Head and Neck surgery. Sensitivity, specificity, negative and positive predictive values, and area under Receiver Operating Curves (AUC-ROC) were calculated with 95% confidence intervals with respect to the histological diagnosis. Logistic regression with an imputation model for missing data was applied., Results: 261 patients aged 34-91 years participated; 79 (30.3%) with non-neoplasia (i.e., inflammation, papilloma, hyperkeratosis) and 182 (69.7%) neoplasia, hereof 95 (36.4%) with GPL and 87 (33.3%) with T1a glottic cancer. Data from 188 VS, 60 HSDI, 100 preoperative EE, 209 intraoperative EE, and 234 SI were analyzed. In the complete case analysis the AUC-ROC of each diagnostic test was low, but increased when the tests were combined and especially if the combination included EE. However, multinomial logistic regression with imputation showed significant association (p < 0.05) only between age, male gender, and perpendicular vasculature in intraoperative EE, and the endpoint neoplasia., Conclusions: Intraoperative EE was the most accurate diagnostic method in detecting neoplasia. The prediction ability of methods applied preoperatively was more limited, but improved when test modalities were combined.

Background: The pediatric voice handicap index (pVHI) questionnaire was developed in 2006 to provide parental information regarding the impact of a voice disorder on their child's life., Objectives: The aim of this study was to make a Danish version of the original American pVHI and to validate the Danish pVHI by evaluating its internal consistency and reliability., Materials and Methods: The original version of the pVHI was translated into Danish. Nineteen parents of dysphonic children, diagnosed in a tertiary otolaryngology hospital department, and 43 parents of children without known voice disorder (control group) completed the questionnaire. The internal consistency, content validity including comparisons of the scores in the two groups and the test-retest reliability were assessed through statistical analysis., Results: The total pVHI scores significantly differed between the group of parents with dysphonic children and the group of parents with children without known voice disorder (p < 0.001). The internal consistency showed an excellent consistency (Chronbach's α > 0.9) of the three subdomains score and the total pVHI score. The test-re-test reliability of the total pVHI score was "strong" with a Pearson's correlation coefficient of 0.97., Conclusions and Significance: The Danish pVHI is a valid and reliable instrument to assess the parents' perception of the impact of a voice disorder on a child's physical, social and emotional well-being., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: The World Health Organization classification (WHOC) 2017 of low-grade versus high-grade laryngeal dysplasia recently replaced the previous WHOC 2005 of mild, moderate, and severe dysplasia and carcinoma in situ. Our objectives were to compare the interrater agreement of the WHOC 2017 with that of the WHOC 2005 and to test the intra-rater agreement of the WHOC 2005., Methods: Two expert head and neck pathologists rated 211 tissue samples that were initially diagnosed with laryngeal precursor lesions. The samples were rated twice according to the WHOC 2005 and once according to the WHOC 2017; estimates of interrater and intrarater agreements were calculated with kappa statistics., Results: The crude intrarater agreements using the WHOC 2005 were 0.93 for rater 1 and 0.62 for rater 2. The corresponding unweighted kappa values were 0.90 (95% confidence interval [CI], 0.86-0.95) for rater 1 and 0.43 (95% CI, 0.35-0.54) for rater 2, whereas the standard linear weighted kappa values were 0.93 (95% CI, 0.90-0.97) for rater 1 and 0.60 (95% CI, 0.53-0.69) for rater 2. The crude interrater agreement for the WHOC 2005 was 0.57, with a corresponding unweighted kappa value 0.38 (95% CI, 0.31-0.48) and a standard linear weighted kappa value 0.52 (95% CI, 0.42-0.60). The crude interrater agreement for the WHOC 2017 was 0.83, with a corresponding unweighted kappa value 0.45 (95% CI, 0.31-0.59) and a standard linear weighted kappa value 0.46 (95% CI, 0.30-0.60)., Conclusion: Our results indicate difficulties in providing reliable diagnosis of laryngeal precursor lesions, even with experienced head and neck pathologists and the application of a newly revised classification system., Level of Evidence: 4. Laryngoscope, 128:2375-2379, 2018., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: The five Nordic countries with a population of 27 M people form a rather homogenous region in terms of health care. The management of head and neck cancer is centralized to the 21 university hospitals in these countries. Our aim was to gain an overview of the volume and role of transoral robotic surgery (TORS) and to evaluate the need to centralize it in this area as the field is rapidly developing. Materials and Methods: A structured questionnaire was sent to all 10 Departments of Otorhinolaryngology-Head and Neck Surgery in the Nordic countries having an active programme for TORS in December 2017. Results: The total cumulative number of performed robotic surgeries at these 10 Nordic centers was 528 and varied between 5 and 240 per center. The median annual number of robotic surgeries was 38 (range, 5-60). The observed number of annually operated cases remained fairly low (<25) at most of the centers. Conclusions: The present results showing a limited volume of performed surgeries call for considerations to further centralize TORS in the Nordic countries.

Objectives: The Ni classification of vascular change from 2011 is well documented for evaluating pharyngeal and laryngeal lesions, primarily focusing on cancer. In the planning of surgery it may be more relevant to differentiate neoplasia from non-neoplasia. We aimed to evaluate the ability of the Ni classification to predict laryngeal or hypopharyngeal neoplasia and to investigate if a changed cutoff value would support the recent European Laryngological Society (ELS) proposal of perpendicular vascular changes as indicative of neoplasia., Data Sources: PubMed, Embase, Cochrane, and Scopus databases., Review Methods: A systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement. We systematically searched for publications from 2011 until 2016. All retrieved studies were reviewed and qualitatively assessed. The pooled sensitivity and specificity of the Ni classification with two different cutoffs were calculated, and bubble and summary receiver operating characteristics plots were created., Results: The combined sensitivity of five studies (n = 687) with Ni type IV-V defined as test-positive was 0.89 (95% confidence interval [CI]: 0.76-0.95), and specificity was 0.82 (95% CI: 0.72-0.89). The equivalent combined sensitivity of four studies (n = 624) with Ni type V defined as test-positive was 0.82 (95% CI: 0.75-0.87), and specificity was 0.93 (95% CI: 0.82-0.97)., Conclusions: The diagnostic accuracy of the Ni classification in predicting neoplasia was high, without significant difference between the two analyzed cutoff values. Implementation of the proposed ELS classification of vascular changes seems reasonable from a clinical perspective, with comparable accuracy. Attention must be drawn to the accompanying risk of exposing patients to unnecessary surgery. Laryngoscope, 128:168-176, 2018., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Introduction: Although vascular lesions are relatively common in head and neck, they are rarely seen in the retropharyngeal space. Frequent symptoms include mass sensation, dysphagia, dyspnea, snoring, and oral bleeding., Presentation of Case: A 31-year-old male was referred from his general practitioner with mass sensation in the throat, increasing snoring, and changing resonance of his voice. Flexible laryngoscopy revealed a large mass extending from the nasopharynx to the hypopharynx, primarily involving retropharyngeal and right parapharyngeal areas, resulting in a significant narrowing. The malformation was resected with good result using a transoral robot-assisted surgical approach. At 1-year follow-up, the patient was symptom free; however, some residual rhinopharyngeal lesion was seen., Discussion: Management strategies include surgical removal, corticosteroid injection, chemotherapy, and cryotherapy. Different surgical approaches have been used over the years., Conclusion: Transoral robotic surgery was successful, providing minimally invasive access with good visualization., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We introduce a density-based multilevel Hartree-Fock (HF) method where the electronic density is optimized in a given region of the molecule (the active region). Active molecular orbitals (MOs) are generated by a decomposition of a starting guess atomic orbital (AO) density, whereas the inactive MOs (which constitute the remainder of the density) are never generated or referenced. The MO formulation allows for a significant dimension reduction by transforming from the AO basis to the active MO basis. All interactions between the inactive and active regions of the molecule are retained, and an exponential parametrization of orbital rotations ensures that the active and inactive density matrices separately, and in sum, satisfy the symmetry, trace, and idempotency requirements. Thus, the orbital spaces stay orthogonal, and furthermore, the total density matrix represents a single Slater determinant. In each iteration, the (level-shifted) Newton equations in the active MO basis are solved to obtain the orbital transformation matrix. The approach is equivalent to variationally optimizing only a subset of the MOs of the total system. In this orbital space partitioning, no bonds are broken and no a priori orbital assignments are carried out. In the limit of including all orbitals in the active space, we obtain an MO density-based formulation of full HF.

Malignancies of the nasal cavity and paranasal sinuses are well known, but have uncommon presentations. Late diagnosis and local extension are significant prognostic factors associated with a poorer treatment outcome. Thus, refinements of the diagnostic procedures to enhance the sensitivity of the clinical evaluation are desirable. We here describe a case of endonasal lymphoma, in which the lesion was hardly visible and initially ignored at ordinary white light (WLI) nasoendoscopy, but easily recognisable, clearly pathogenic and well demarcated when illuminated with narrow band imaging (NBI) at a later session. In general, with regard to mucosal-derived pathology of the upper aerodigestive tract, the diagnostic gain of NBI-assisted endoscopy in comparison with that of WLI has been proved in several articles. The focus has however been on neoplasm in laryngopharynx and oesophagus. The authors recommend broadening the use of NBI to include all evaluations of nasal mucosa, when malignancy is suspected., Competing Interests: Competing interests: None declared., (2017 BMJ Publishing Group Ltd.)

In a recent work [P. Baudin and K. Kristensen, J. Chem. Phys. 144, 224106 (2016)], we introduced a local framework for calculating excitation energies (LoFEx), based on second-order approximated coupled cluster (CC2) linear-response theory. LoFEx is a black-box method in which a reduced excitation orbital space (XOS) is optimized to provide coupled cluster (CC) excitation energies at a reduced computational cost. In this article, we present an extension of the LoFEx algorithm to the calculation of CC2 oscillator strengths. Two different strategies are suggested, in which the size of the XOS is determined based on the excitation energy or the oscillator strength of the targeted transitions. The two strategies are applied to a set of medium-sized organic molecules in order to assess both the accuracy and the computational cost of the methods. The results show that CC2 excitation energies and oscillator strengths can be calculated at a reduced computational cost, provided that the targeted transitions are local compared to the size of the molecule. To illustrate the potential of LoFEx for large molecules, both strategies have been successfully applied to the lowest transition of the bivalirudin molecule (4255 basis functions) and compared with time-dependent density functional theory.

We report porting of the Divide-Expand-Consolidate Resolution of the Identity second-order Møller-Plesset perturbation (DEC-RI-MP2) method to the graphic processing units (GPUs) using OpenACC compiler directives. It is shown that the OpenACC compiler directives implementation efficiently accelerates the rate-determining step of the DEC-RI-MP2 method with minor implementation effort. Moreover, the GPU acceleration results in a better load balance and thus in an overall scaling improvement of the DEC algorithm. The resulting cross-platform hybrid MPI/OpenMP/OpenACC implementation has scalable and portable performance on heterogeneous HPC architectures. The GPU-enabled code was benchmarked using a reduced version of the S12L test set of Stefan Grimme (Grimme, Chem. Eur. J. 2012, 18, 9955) consisting of supramolecular complexes up to 158 atoms and 4292 contracted basis functions (cc-pVTZ). The test set results demonstrate the general applicability of the DEC-RI-MP2 method showing results consistent with the DEC-RI-MP2 introductory paper (Baudin et al., J. Chem. Phys. 2016, 144, 054102) on molecules of complicated electronic structures. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The divide-expand-consolidate resolution of the identity second-order Møller-Plesset perturbation (DEC-RI-MP2) theory method introduced in Baudin et al. [J. Chem. Phys. 144, 054102 (2016)] is significantly improved by introducing the Laplace transform of the orbital energy denominator in order to construct the double amplitudes directly in the local basis. Furthermore, this paper introduces the auxiliary reduction procedure, which reduces the set of the auxiliary functions employed in the individual fragments. The resulting Laplace transformed divide-expand-consolidate resolution of the identity second-order Møller-Plesset perturbation method is applied to the insulin molecule where we obtain a factor 9.5 speedup compared to the DEC-RI-MP2 method.

An atomic orbital density matrix based response formulation of the nuclei-selected approach of Beer, Kussmann, and Ochsenfeld [J. Chem. Phys. 134, 074102 (2011)] to calculate nuclear magnetic resonance (NMR) shielding tensors has been developed and implemented into LSDalton allowing for a simultaneous solution of the response equations, which significantly improves the performance. The response formulation to calculate nuclei-selected NMR shielding tensors can be used together with the density-fitting approximation that allows efficient calculation of Coulomb integrals. It is shown that using density-fitting does not lead to a significant loss in accuracy for both the nuclei-selected and the conventional ways to calculate NMR shielding constants and should thus be used for applications with LSDalton.

The membrane receptor megalin is crucial for normal fetal development. Besides its expression in the developing fetus, megalin is also expressed in the human placenta. Similar to its established function in the kidney proximal tubules, placental megalin has been proposed to mediate uptake of vital nutrients. However, details of megalin expression, subcellular localization, and function in the human placenta remain to be established. By immunohistochemical analyses of first trimester and term human placenta, we showed that megalin is predominantly expressed in cytotrophoblasts, the highly proliferative cells in placenta. Only limited amounts of megalin could be detected in syncytiotrophoblasts and least in term placenta syncytiotrophoblasts. Immunocytochemical analyses furthermore showed that placental megalin associates with structures of the endolysosomal apparatus. Combined, our results clearly place placental megalin in the context of endocytosis and trafficking of ligands. However, due to the limited expression of megalin in syncytiotrophoblasts, especially in term placenta, it appears that the main role for placental megalin is not to mediate uptake of nutrients from the maternal bloodstream, as previously proposed. In contrast, our results point toward novel and complex functions for megalin in the cytotrophoblasts. Thus, we propose that the perception of placental megalin localization and function should be revised., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2016 The Histochemical Society.)

We report an implementation of the molecular gradient using the divide-expand-consolidate resolution of the identity second-order Møller-Plesset perturbation theory (DEC-RI-MP2). The new DEC-RI-MP2 gradient method combines the precision control as well as the linear-scaling and massively parallel features of the DEC scheme with efficient evaluations of the gradient contributions using the RI approximation. We further demonstrate that the DEC-RI-MP2 gradient method is capable of calculating molecular gradients for very large molecular systems. A test set of supramolecular complexes containing up to 158 atoms and 1960 contracted basis functions has been employed to demonstrate the general applicability of the DEC-RI-MP2 method and to analyze the errors of the DEC approximation. Moreover, the test set contains molecules of complicated electronic structures and is thus deliberately chosen to stress test the DEC-RI-MP2 gradient implementation. Additionally, as a showcase example the full molecular gradient for insulin (787 atoms and 7604 contracted basis functions) has been evaluated.

We present the DEC-RIMP2-F12 method where we have augmented the Divide Expand-Consolidate resolution-of-the-identity second-order Møller-Plesset perturbation theory method (DEC-RIMP2) [P. Baudin et al., J. Chem. Phys. 144, 054102 (2016)] with an explicitly correlated (F12) correction. The new method is linear-scaling, massively parallel, and it corrects for the basis set incompleteness error in an efficient manner. In addition, we observe that the F12 contribution decreases the domain error of the DEC-RIMP2 correlation energy by roughly an order of magnitude. An important feature of the DEC scheme is the inherent error control defined by a single parameter, and this feature is also retained for the DEC-RIMP2-F12 method. In this paper we present the working equations for the DEC-RIMP2-F12 method and proof of concept numerical results for a set of test molecules.

We augment the recently introduced same number of optimized parameters (SNOOP) scheme [K. Kristensen et al., J. Chem. Phys. 142, 114116 (2015)] for calculating interaction energies of molecular dimers with an F12 correction and generalize the method to enable the determination of interaction energies of general molecular clusters. The SNOOP, uncorrected (UC), and counterpoise (CP) schemes with/without an F12 correction are compared for the S22 test set of Jurečka et al. [Phys. Chem. Chem. Phys. 8, 1985 (2006)]-which consists of 22 molecular dimers of biological importance-and for water and methane molecular clusters. The calculations have been performed using the Resolution of the Identity second-order Møller-Plesset perturbation theory method. We conclude from the results that the SNOOP scheme generally yields interaction energies closer to the complete basis set limit value than the UC and CP approaches, regardless of whether the F12 correction is applied or not. Specifically, using the SNOOP scheme with an F12 correction yields the computationally most efficient way of achieving accurate results at low basis set levels. These conclusions hold both for molecular dimers and more general molecular clusters.

The theoretical foundation for solving coupled cluster singles and doubles (CCSD) amplitude equations to a desired precision in terms of independent fragment calculations using restricted local orbital spaces is reinvestigated with focus on the individual error sources. Four different error sources are identified theoretically and numerically and it is demonstrated that, for practical purposes, local orbital spaces for CCSD calculations can be identified from calculations at the MP2 level. The development establishes a solid theoretical foundation for local CCSD calculations for the independent fragments, and thus for divide-expand-consolidate coupled cluster calculations for large molecular systems with rigorous error control. Based on this theoretical foundation, we have developed an algorithm for determining the orbital spaces needed for obtaining the single fragment energies to a requested precision and numerically demonstrated the robustness and precision of this algorithm.

The Resolution of the Identity second-order Møller-Plesset perturbation theory (RI-MP2) method is implemented within the linear-scaling Divide-Expand-Consolidate (DEC) framework. In a DEC calculation, the full molecular correlated calculation is replaced by a set of independent fragment calculations each using a subset of the total orbital space. The number of independent fragment calculations scales linearly with the system size, rendering the method linear-scaling and massively parallel. The DEC-RI-MP2 method can be viewed as an approximation to the DEC-MP2 method where the RI approximation is utilized in each fragment calculation. The individual fragment calculations scale with the fifth power of the fragment size for both methods. However, the DEC-RI-MP2 method has a reduced prefactor compared to DEC-MP2 and is well-suited for implementation on massively parallel supercomputers, as demonstrated by test calculations on a set of medium-sized molecules. The DEC error control ensures that the standard RI-MP2 energy can be obtained to the predefined precision. The errors associated with the RI and DEC approximations are compared, and it is shown that the DEC-RI-MP2 method can be applied to systems far beyond the ones that can be treated with a conventional RI-MP2 implementation.

We propose a reformulation of the traditional (T) triples correction to the coupled cluster singles and doubles (CCSD) energy in terms of local Hartree-Fock (HF) orbitals such that its structural form aligns with our recently developed linear-scaling divide-expand-consolidate (DEC) coupled cluster family of local correlation methods. In a DEC-CCSD(T) calculation, a basis of local occupied and virtual HF orbitals is used to partition the correlated calculation on the full system into a number of independent atomic fragment and pair fragment calculations, each performed within a truncated set of the complete orbital space. In return, this leads to a massively parallel algorithm for the evaluation of the DEC-CCSD(T) correlation energy, which formally scales linearly with the size of the full system and has a tunable precision with respect to a conventional CCSD(T) calculation via a single energy-based input threshold. The theoretical developments are supported by proof of concept DEC-CCSD(T) calculations on a series of medium-sized molecular systems.

ZFR is an ancient and highly conserved chromosome-associated protein from nematodes to mammals, embryologically expressed in most species, with the exception of the nematode Caenorhabditis elegans. The ZFR encodes zinc and RNA binding protein, and in rat, the nuclear-cytoplasmic shuttling ZFR has been found with transport and translation-associated RNA granule-like structures in the somatodendritic compartments of hippocampal neurons. The majority of axons cross the midline before projecting to their contralateral synaptic target and this crossing decision is under tight control. Molecular factors contributing to these processes have been identified, although the mechanisms are not fully understood. In this study, we tested the role of ceZFR in axon guidance using ceZfr RNAi-treated animals to analyse axon midline crossing, axon fasciculation and cord commissures. In adult stages, RNAi-induced depletion of the ceZfr transcript leads to several phenotypes related to axon guidance. A midline crossing defect was observed in the ventral nerve cord (VNC) in axon type D, DD/VD motoneuron axons and axon type 1, interneuron axons. We further detected a dorsal nerve cord (DNC) axon fasciculation. Some ceZfr RNAi-treated animals revealed that cord commissures fail to reach their synaptic target. We provide evidence that ceZFR has a role in axon guidance. When Zfr was depleted by RNAi, the phenotypes are characterized by defects in axon midline crossing, axon defasciculation and cord commissures. Our results thus support the hypothesis that ZFR has essential roles during neurogenesis, and could support early steps of RNA transport and localization through RNA granule formation in the nucleus and/or to their nucleo-cytoplasmic shuttling., (Copyright © 2014 Elsevier B.V. All rights reserved.)